Notice - Release of a revised version of the Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)

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March 27, 2009
Our file number: 09-108207 - 996

Release of a revised version of the Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)

Health Canada is pleased to announce the release of this revised version of its Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs) for another consultation period.

The original draft guidance document (dated January 30^th, 2008) was revised in response to written comments following its release, and based on face-to-face consultations including the Consultation on the Regulatory Framework for SEBs in Aylmer, QC, held on June 5th and 6th, 2008.

Please read the revised Draft Guidance Document in conjunction with the accompanying Questions and Answers document before commenting.

Note: The "Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)" is being published concurrently with the following notices, which describe amendments to existing Data Protection and Patented Medicines (Notice of Compliance) Regulations Guidance Documents that are being made to address SEBs.

• Release of Proposed Revisions to Guidance Document: Data Protection under C.08.004.1 of the Food and Drug Regulations
• Release of Proposed Additions to Guidance Document: Patented Medicines (Notice of Compliance) Regulations

Written comments on the revised draft guidance document should be provided to Health Canada, within 60 days from the date of this notice. These comments may be disclosed publicly. Persons submitting comments should stipulate any parts of the comments that should not be disclosed pursuant to the Access to Information Act (in particular, pursuant to sections 19 and 20 of that Act), the reason why those parts should not be disclosed and the period during which they should remain undisclosed. Representations should also stipulate those parts of the comments for which there is consent to disclosure pursuant to the Access to Information Act.

Comments pertaining to this notice should be directed to:

BGTD_PPD_DPP@HC-SC.GC.CA
Special Projects Unit,
Policy and Promotion Division
Biologics and Genetic Therapies Directorate
Health Canada
Address Locator 0702A
200 Tunney's Pasture Driveway
Ottawa ON, K1A 0L2

Telephone: 613-946-5155
Fax: 613-952-5364

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

Draft Date: 2009/03/27

Health Products and Food Branch

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada's mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach.  Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification.  Alternate approaches should be discussed in advance with the relevant programme area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product.  Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidance documents.

Table Of Contents

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1.0 Introduction

1.1 Objective

Health Canada, the federal regulatory authority that evaluates the safety, efficacy, and quality of health products available in Canada, recognises that with the expiration of patents for biologic drugs, there will be the introduction of subsequent entry versions of biologic drugs.  This document provides guidance to sponsors on information and regulatory requirements for subsequent entry biologics (SEBs) in Canada.

1.2 Scope and application

The concept of an SEB applies to all biologic drug submissions where the sponsor seeks authorization for sale based on demonstrated similarity to a biologic drug that was authorized for sale in Canada and relies, in part, on prior information regarding the authorized innovative biologic drug in order to present a reduced clinical and non-clinical package as part of the submission.

An SEB will only be authorized if a submission demonstrates similarity based on a direct or indirect comparison to such an authorized innovative biologic drug.

To provide flexibility to sponsors, Health Canada will, in appropriate and special circumstances, permit the use of a reference biologic drug that is not authorized for sale in Canada to be used in the demonstration of similarity between the SEB and the product authorized for sale in Canada. However, in all instances where a non-Canadian reference product is used, the submission must explicitly and clearly explain the link between the reference product and the product authorized for sale in Canada (please refer to section 2.1.3.1 for more information).

The demonstration of similarity depends upon detailed and comprehensive product characterization. The information requirements apply to biologic drugs that contain, as their active substances, well characterized proteins derived through modern biotechnological methods such as use of recombinant DNA and/or cell culture.  

The following are additional criteria to determine the scope of eligible products:

• a suitable reference biologic drug exists that: a) was originally authorized for sale based on a complete data package; and b) has significant safety and efficacy data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data;  
• the product can be well characterized by a set of modern analytical methods; and
• the biologic drug, through extensive characterization and analysis,  can be judged similar to the reference biologic drug by meeting an appropriate set of pre-determined criteria. 

Products employing clearly different approaches to manufacture than the reference biologic drug (for example, use of transgenic organisms versus cell culture) will not be eligible for authorization as SEBs.

1.3 Policy statements

The following outlines the fundamental concepts and principles of the regulatory framework for SEBs.

1.3.1 The information and submission requirements for authorization of SEBs outlined in this document should permit a sponsor to satisfy the expectation of 'sufficient information' as outlined in sections C.08.002 (2) of the Food and Drug Regulations¹ . The onus is on the sponsor to provide the necessary evidence to support all aspects of an application for authorization.

1.3.2 Regulatory decisions regarding SEBs will be based on scientific and regulatory principles existing within the Food and Drugs Act and Regulations. The principles within the existing regulatory frameworks for biologic, pharmaceutical, and generic pharmaceutical drugs are used as the basis for the regulatory framework for SEBs.

1.3.3 The basis for a product being authorized as an SEB hinges on the ability to demonstrate similarity to a suitable reference biologic drug.

1.3.4 SEBs are not "generic biologics" and many characteristics associated with the authorization process and marketed use for generic pharmaceutical drugs do not apply. Authorization of an SEB is not a declaration of pharmaceutical and/or therapeutic equivalence to the reference biologic drug.

1.3.5 An SEB will only be authorized based on a submission that makes either a direct or indirect comparison to an innovator product previously authorized for sale in Canada. Hence all the laws, patent and intellectual property principles outlined within the Food and Drug Regulations (Data Protection), and Patented Medicines (Notice of Compliance) Regulations are applicable to SEBs.

1.3.6 Once a Notice of Compliance (NOC) is granted, the SEB is a new biologic drug and regulated like any other new biologic drug. Therefore, an SEB cannot be used as a reference biologic drug.

1.4 Definitions

Biologic drug (Médicament biologique)
Biologics are drugs listed in Schedule D to the Food and Drugs Act. 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.

Subsequent Entry Biologic (SEB) (Produit biologique ultérieur (PBU))
A subsequent entry biologic is a biologic drug that would enter the market subsequent to, and 'similar' to an innovator product authorized for sale in Canada. A subsequent entry biologic relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug.

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.  A specification establishes the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to in order 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 authorized for sale by regulatory authorities as conditions of approval.

Reference biologic drug (Médicament biologique de référence)
A reference biologic drug is a biologic drug already authorized on the basis of a complete quality, non-clinical, and clinical data package. A reference biologic drug is chosen by the manufacturer of the SEB to demonstrate, in part, similarity between the SEB and the drug authorized for sale in Canada. 

Abbreviations and Acronyms
ADR = Adverse Drug Reaction
BGTD = Biologics and Genetic Therapies Directorate
C&M = Chemistry and Manufacturing
CTA = Clinical Trial Application
CTD = Common Technical Document
HPFB = Health Products and Food Branch
NDS = New Drug Submission
NOC = Notice of Compliance
PK/PD = pharmacokinetic/pharmacodynamic
PM = Product Monograph
PSUR = Periodic Safety Update Reports
QOS = Quality Overall Summary
SEB = Subsequent Entry Biologic

1.5 Background

Biologic drugs have contributed to the health of Canadians through their use as treatments in the management of various complex diseases and medical conditions. The expiration of patents and/or data protection for some biologic drugs is ushering in an era for biologic drugs that are subsequent entry versions of authorized innovative biologic drug. Sponsors will seek market authorization by relying partially on available data or information about an innovative biologic drug authorized for sale in Canada.

Biologic drugs, unlike pharmaceutical drugs which are synthesized, are derived through the metabolic activity of living organisms and are variable and structurally complex. They are manufactured from animals, microorganisms, or through the use of animals or microorganisms. Biologics are typically labile and sensitive to changes in manufacturing processes. Biological source materials, production cells, or their fermentation media can present risks, such as the initial presence of pathogens or the growth of adventitious agents such as viruses. Because of this, careful attention is paid to raw material controls, viral/bacterial inactivation or clearance during product purification and product testing. Changes to source materials, manufacturing processes, equipment, or facilities can result in significant unexpected changes to the intermediate and/or final product. 

The term "subsequent entry biologic" (SEB) is used by Health Canada to describe a biologic drug that is authorized for sale based on a demonstration of similarity to an innovative  biologic drug authorized for sale in Canada. Accordingly, an SEB will in all instances be a subsequent entrant onto the Canadian market. SEB products will only be authorized for sale based on new drug submissions in which there is a direct or indirect comparison between the SEB and the innovative biologic drug for the purposes of demonstrating similarity. By definition, an SEB relies on prior information from the reference biologic drug and an approval could be granted based on a reduced amount of clinical information tailored to each class of products and/or case. The term, subsequent entry biologic, was chosen as an alternative to "biogeneric or generic biologic" to clearly indicate a distinction between the regulatory process (and/or product characteristics) for SEBs and the regulatory processes that is currently used for generic pharmaceutical drugs.

It is generally accepted that the principles and procedures for the authorization of generic pharmaceutical drugs are unacceptable for biologic drugs. Hence, along with a full complement of quality information, some original non-clinical and clinical data is required to support an SEB application. The type and extent of non-clinical and clinical data required to support an application will depend on existing knowledge of the reference product, and on the nature of the indication being claimed.

The Biologics and Genetic Therapies Directorate (BGTD) within the Health Products and Food Branch (HPFB) of Health Canada is the regulator of biologic drugs. BGTD provides regulatory oversight for biologics with its comprehensive reviews of biologic submissions covering quality, safety, and efficacy, Lot Release Program and On-site Evaluation Program.

2.0 Guidance For Implementation

2.1  General

2.1.1 Applicable Regulations

Food and Drug Regulations C.08.002 (1)(a):No person shall sell or advertise a new drug unless the manufacturer has filed with the Minister a New Drug Submission (NDS) relating to the new drug that is satisfactory to the Minister.

Food and Drug Regulations 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 a new drug.

Conforming to the guidance provided in this document should permit a sponsor to satisfy the requirements of C.08.002 of the Food and Drug Regulations and Patented Medicines (Notice of Compliance) Regulations.

2.1.2 Clinical Indications

The clinical indications granted to an SEB are based on data provided by the sponsor. The SEB shall be granted indications of the reference biologic drug for which supporting data is provided. An SEB sponsor may be granted additional indications for which full clinical trial data has not been provided, where the mechanism of action strongly supports an indication. 

Factors to be considered in granting clinical indications, while assessed on a case-by-case basis, include:

• the product,
• the level of reliance on the reference biologic drug in the development programme for the product,
• the type of clinical trial carried out in support of the product,
• the route of administration, dosing range, the demonstrated level of similarity between the SEB and the reference biologic drug, and;
• the availability of post-market information and the benefits/risks associated with such extrapolation from a clinical perspective. A written rationale for the extrapolation(s) must be provided by the SEB sponsor.

An SEB product sponsor should be eligible to apply for indication(s) within those granted to the reference biologic drug in Canada. Any claims made by the SEB sponsor shall be supported by suitable scientific data.

Where a clinical indication is not held by the reference biologic drug or a clinical indication has been previously denied in Canada for a member of a particular class, full clinical trial data should be provided in support of the submission information must be filed.

2.1.3  Reference biologic drug

The following provides general guidance on factors affecting the choice of reference biologic drug

• The onus is on the sponsor to demonstrate that the chosen reference biologic drug is suitable to support the submission
• The reference biologic drug must be authorized for sale and should marketed in Canada.
• The chosen reference biologic drug should be used throughout the studies supporting the safety, quality, and efficacy of the product (i.e. in the developmental programme for the SEB).
• The dosage form, strength, route of administration of the SEB should be the same as that of the reference biologic drug.
• The active substance (medicinal ingredient) of the reference biologic drug and the SEB must be shown to be similar.
• An SEB must not be used as a reference biologic drug.
• The reference biologic drug should 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 Considerations for use of a Non-Canadian reference biologic drug

Although an SEB will only be authorized based on a submission that demonstrates similarity through a direct or indirect comparison to a biologic drug authorized for sale in Canada.

Health Canada will, in the following circumstances, permit the use of a reference biologic drug that is not authorized for sale in Canada, as part of the demonstration of similarity between the SEB and the reference product.

• Where a non-Canadian reference biologic drug is contemplated, the sponsor is encouraged to contact Health Canada early in the drug development process. The sponsor also has the responsibility of ensuring that the chosen non-Canadian reference biologic drug has suitable information about it to support the submission.
• The use of a reference biologic drug that is not authorized for sale in Canada may be considered on request to the Minister as part of the evidence for demonstrating similarity between the SEB and the approved product in Canada. However, in all instances, thesubmission must include sufficient information to explicitly explain the link between the reference biologic drug used in any comparative studies to the innovator product approved in Canada.
• Non-Canadian reference biologic drug(s) from jurisdictions that have an established relationship with HPFB are preferred.
• If a non-Canadian reference biologic product is considered, it is preferred that it is widely marketed in a jurisdiction that formally adopts International Conference on Harmonization (ICH) guidelines and has regulatory standards and principles for evaluation of medicines, post-market surveillance activities, and approach to comparability that are similar to Canada.
• In order to sufficiently explain the link between the non-Canadian reference biologic drug and the version of the product authorized for use in Canada, it must be documented in the submission that the non-Canadian reference biologic drug is marketed by the same innovator company or corporate entity which is approved to market the medicinal ingredient in the same dosage form in Canada, or that it is marketed through a licensing arrangement with the innovator company or corporate entity which currently markets the version of the product approved in Canada.
• The reference biologic drug used in clinical studies in Canada, will require complete chemistry and manufacturing information as per C.05.005 of the Food and Drug Regulations.

2.1.4 Patents, Intellectual Property, and Data Protection

An SEB will only be approved based on a submission that makes either a direct or indirect comparison to an innovative biologic product previously authorized for sale in Canada. As such, SEBs shall be subject to existing laws and regulations as outlined in the PM(NOC) Regulations and C.08.004.1 of the Food and Drug Regulations, and related guidance documents entitled, "Draft Guidance Document: Data Protection under C.08.004.1 of the Food and Drug Regulations" and "Guidance Document: Patented Medicines (Notice of Compliance) Regulations".

2.1.5  Review time

The target time for review of an SEB will be the same as that for an NDS. Please refer to the Management of Drug Submission Guidance for further details on review timelines.

2.1.6  Consultation with Health Canada

Sponsors of SEBs are encouraged to consult with BGTD for regulatory guidance at any stage of the development of an SEB.
Contact Information:

Biologics and Genetic Therapies Directorate
Centre for Policy and Regulatory Affairs Division
Regulatory Affairs Division
Address Locator: 0701A
200 Tunney's Pasture Driveway
Ottawa, Ontario K1A 0K9
Phone: 613-957-1722
Fax: 613-941-0364
Email: BGTD_RAD_Enquiries@hc-sc.gc.ca

2.2 Information requirements for Clinical Trial Applications (CTA)

Clinical trials conducted in Canada involving SEBs are subject to Part C, Division 5 of the Food and Drug Regulations, which outlines the requirements applicable to the sale and importation of drugs for use in human clinical trials in Canada. Clinical Trial Applications (CTAs) should be submitted in accordance with Health Canada's Guidance for Clinical Trial Sponsors: Clinical Trial Applications and the Clinical Trials Manual. 

Sponsors need to include all information identified in C.05.005 of the Food and Drug Regulations in their application for authorization.

2.3 Information for New Drug Submissions (NDS)

Part C, Division 8 of the Food and Drug Regulations sets out the requirements for the sale of new drugs in Canada, including SEBs, 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 Food and Drug Regulations outline the requirements for an NDS. 

2.3.1 Quality information

In addition to a full chemistry and manufacturing (C&M) data package that is expected for a standard new biologic drug, the SEB package should provide extensive data on the demonstration of similarity with the reference biologic drug, including extensive side-by-side characterization of the SEB and the chosen reference biologic drug.  For consideration as an SEB, similarity should be primarily deduced from comprehensive quality studies.

If the reference drug substance used for characterization is isolated from a formulated reference drug product, additional studies must demonstrate that the drug substance is not changed by the isolation process.  One approach to qualifying the isolation process is to use the process on the formulated SEB drug product and compare the isolated (de-formulated) SEB drug substance to the SEB drug substance obtained prior to formulation. 

2.3.1.1 Considerations for the comparability exercise

Although the comparison of two independent products is outside of the scope of ICH Q5E, many of the principles and approaches are applicable.

The goal of the comparability exercise is to ascertain whether the SEB and the chosen reference biologic drug are similar in terms of quality, and thus provide support for a possible conclusion of similarity for safety and efficacy.  To meet this goal, the product should be evaluated at the process steps most appropriate to detect a difference in the quality attributes.  This may entail evaluating both the drug substance and the drug product. The extent of the studies necessary to demonstrate comparability will depend on:

• The nature of the product;
• The availability of suitable analytical techniques to detect potential product differences; and,
• The relationship between quality attributes and safety and efficacy, based on overall non-clinical and clinical experience. 

When considering the similarity of products, the manufacturer should evaluate, for example:

• Relevant physicochemical and biological characterization data regarding quality attributes;
• Results from analysis of relevant samples from the appropriate stages of the manufacturing process (i.e., drug substance, and drug product);
• Stability data, including those generated from accelerated or stress conditions, to provide insight into potential product differences in the degradation pathways of the drug product and, hence, potential differences in product-related substances and product-related impurities;
• Data obtained from multiple batches of the SEB and of the reference biologic drug. 

In addition to evaluating the data, the manufacturer should also consider if the results provide insights regarding:

• Critical control points in the manufacturing process that affect product characteristics;
• Adequacy of the in-process controls including critical control points and in-process testing: in-process controls for the SEB should be confirmed, modified, or created, as appropriate, to maintain the quality of the product;
• The type and extent of data to be derived from non-clinical and clinical studies on the drug product.

2.3.1.2 Quality considerations

Analytical Techniques
The battery of tests for the comparability exercise should be carefully selected and optimised to maximise the potential for detecting relevant differences in the quality attributes of the SEB and the reference biologic drug.  To address the full range of physicochemical properties or biological activities, it may be appropriate to apply more than one analytical procedure to evaluate the same quality attribute (i.e., molecular weight, impurities, secondary/tertiary structures).  In such cases, each method should employ different physicochemical or biological principles to collect data for the same parameter to maximise the possibility that differences in the SEB relative to the reference biologic drug may be detected.

It can be difficult to ensure that the set of analytical procedures originally chosen for the SEB will be able to detect differences from the reference biologic drug due to the limitations of the assays (e.g., precision, sensitivity, and specificity) and the complexity of some products due to molecular heterogeneity.  Consequently, the manufacturer should determine:

• Whether or not existing tests remain appropriate for their intended use or should be modified.  For example, when there is a different impurity profile expected in the host cell proteins for the reference biologic drug, the manufacturer should confirm that the test used to quantitate host cell proteins in the SEB is still suitable for its intended purpose in the comparability studies.  It may be appropriate to modify the existing test to better detect the new impurities;
• The need to add new tests, as a result of differences in quality attributes, that the existing methods are not capable of measuring.  That is, when specific changes in quality attributes are expected as a result of a process difference relative to the reference biologic drug (e.g., different raw material or different chromatographic purification step), it may be appropriate to develop new analytical procedures, i.e., to employ additional analytical techniques above and beyond those used previously for characterization or routine testing. 
• Whether the results from the comparability studies should cause reflection regarding the current tests used for the SEB and perhaps influence changes.

An early decision on the choice of reference biologic drug may allow selection of the most appropriate set of analytical procedures for development of the SEB and the eventual comparability exercise. 

The measurement of quality attributes in characterization studies does not necessarily entail the use of validated assays, but the assays should be scientifically sound and provide results that are reliable. Those methods used to measure quality attributes for batch release should be validated in accordance with ICH guidelines (ICH Q2A, Q2B, Q5C, Q6B), as appropriate. 

Characterization
Characterization of a biotechnological/biological product by appropriate techniques, as described in ICH Q6B, includes the determination of physicochemical properties, biological activity, immunochemical properties (if any), purity, impurities, contaminants, and quantity. 

When conducting a comparability study, a complete side-by-side characterization is generally warranted to directly compare the SEB and the reference biologic drug.  However, additional characterization may be indicated in some cases.  For example, when the product characterization profiles differ, the significance of these differences should be evaluated.

Each of the following criteria should be considered as a key point in the conduct of the comparability exercise:

The manufacturer should consider the concept of the desired product (and its variants) as defined in ICH Q6B when designing and conducting a comparability exercise.  The complexity of the molecular entity with respect to the degree of molecular heterogeneity should also be considered.  The manufacturer should attempt to determine that higher order structure (secondary, tertiary, and quaternary structure) is comparable.  If the appropriate higher order structural information cannot be obtained, a relevant biological activity assay (see biological activity below) could indicate a correct conformational structure.

Biological Activity
Biological assay results can serve multiple purposes in the confirmation of product quality attributes that are useful for characterization and batch analysis, and in some cases, could serve as a link to clinical activity.  The manufacturer should consider the limitations of biological assays, such as high variability, that may prevent detection of differences between two similar products. 

In cases where the biological assay also serves as a complement to physicochemical analysis, for example, as a surrogate assay for higher order structure, the use of a relevant biological assay with appropriate precision and accuracy may provide a suitable approach to confirm that a change in specific higher order structure has not occurred.  Where physicochemical or biological assays are not considered adequate to confirm that the higher order structure is maintained, data from non-clinical or clinical studies may be supportive.  However, too much reliance on such studies may indicate that consideration as an SEB is not appropriate. 

When the products being compared have multiple biological activities, manufacturers should perform a set of relevant functional assays designed to evaluate the range of activities.  For example, certain proteins possess multiple functional domains that express enzymatic and receptor mediated activities. In such situations, manufacturers should evaluate all relevant functional activities.

Where one or more of the multiple activities are not sufficiently correlated with clinical safety or efficacy or if the mechanism of action is not understood, the manufacturer should justify that non-clinical or clinical activity of the SEB is not compromised. 

Immunochemical Properties
When immunochemical properties are part of the characterization (e.g., for antibodies or antibody-based products), the manufacturer should confirm that the SEB is comparable to the reference biologic drug in terms of the specific properties.

Purity, Impurities, and Contaminants
The combination of analytical procedures selected should provide data to allow evaluation of whether there is a difference in the purity and impurity profiles. 

If differences are observed in the purity and impurity profiles of the SEB relative to the reference biologic drug, the differences should be evaluated to assess their potential impact on safety and efficacy.  Where the SEB exhibits different impurities, those impurities should be identified and characterised when possible.  Depending on the impurity type and amount, the conduct of non-clinical and clinical studies will help to confirm that there is no adverse impact on safety or efficacy of the SEB. 

Contaminants should be strictly avoided and/or suitably controlled with appropriate in-process acceptance criteria or action limits for drug substance or drug product.  New contaminants should be evaluated to assess their potential impact on the quality, safety, and efficacy of the product. 

Specifications
The tests and analytical procedures chosen to define drug substance or drug product specifications alone are not considered adequate to assess product differences since they are chosen to confirm the routine quality of the product rather than to fully characterise it.  The manufacturer should confirm that the specifications chosen for the SEB are appropriate to ensure product quality.

Stability
For certain manufacturing processes, even slight differences in the production procedures used for the SEB and reference biologic drug may cause differences in the stability of the products. 

Proteins are frequently sensitive to changes, such as those made to buffer composition, processing and holding conditions, and the use of organic solvents.  Therefore, real-time/real temperature, side-by-side stability studies should be conducted on the SEB and reference biologic drugs 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 SEB and reference biologic drug that are not readily detectable by the characterization studies.  For example, the presence of trace amounts of a protease may only be detected by product degradation that occurs over an extended time period.  Or in some cases, divalent ions leached from the container closure system may change the stability profile because of the activation of trace proteases.

Accelerated and stress stability studies are often useful tools to establish degradation profiles and can therefore contribute to a direct comparison of an SEB and the reference biologic drug.  The results may show product differences that warrant additional evaluation. The results may also identify conditions indicating that additional controls should be employed in the manufacturing process and during storage of the SEB to eliminate these unexpected differences.  Appropriate studies should be considered to confirm that suitable storage conditions and controls are selected.

ICH Q5C and Q1A(R) should be consulted to determine the conditions for stability studies that provide relevant data for a product-to-product comparison. 

2.3.1.3  Manufacturing process considerations

A well-defined manufacturing process with its associated process controls assures that an acceptable product is produced on a consistent basis. 

Approaches to determining the impact of any process differences will vary with respect to the specific process, the product, the extent of the manufacturer's knowledge of and experience with the process, and development data generated. 

Where details of the manufacturing process for the reference biologic drug are known and can be compared with those for the SEB, such an analysis may help identify which tests should be performed during the comparability exercise.

2.3.1.4 Determination of similarity

The demonstration of similarity does not necessarily signify that the quality attributes of the two products being compared are identical, but that they are highly similar with two consequences: 1) that the existing knowledge of both products is sufficient to predict that any differences in quality attributes should have no adverse impact upon safety or efficacy of the SEB;  and 2) that non-clinical and clinical data previously generated with the reference biologic drug is relevant to the SEB. 

A final determination of similarity can be based on a combination of analytical testing, biological assays, and non-clinical and clinical data.  However, to be considered an SEB, the weight of evidence should be provided by the analytical and biological characterization.

Consideration as an SEB may not be appropriate in the following situations: 

1. the analytical procedures used are not sufficient to discern relevant differences that can impact the safety and efficacy of the product; or
2. the relationship between specific quality attributes and safety and efficacy has not been established, and differences between quality attributes of the SEB and the reference biologic drug are likely to be observed; and,
   and as a result, non-clinical and clinical studies are expected to contribute significantly to a potential determination of similarity.

2.3.1.5 Organization of data

The assessment of similarity should be organized in the Common Technical Document (CTD) as a distinct collection of data in module 3 with an associated section in the Quality Overall Summary (QOS) containing appropriate cross-references.

2.3.1.6 Changes following issuance of the market authorization

Once granted a NOC, an SEB is considered to be a new (stand-alone) product with all of the associated regulatory requirements.  For any changes to the manufacturing process that warrant a demonstration of comparability, the products to be compared will be the pre-change and post-change versions of the SEB.  Comparisons with the original reference biologic drug are not required. 

2.3.2 Non-clinical and Clinical Information

2.3.2.1 General

Non-clinical and clinical requirements outlined for SEB submissions in this guidance document are applicable to SEBs that have been demonstrated to be similar to the chosen reference biologic drug, based on the results of the comparability exercises included in the C&M data package. If the similarity of an SEB to the reference biologic drug cannot be established based on the C&M data package, complete non-clinical and clinical data will be required to support the submission.

This section provides only general guidance on non-clinical and clinical information for SEBs containing well characterized proteins derived through modern biotechnological methods.

The requirements for the drug classes (for example, insulin, growth hormone) may vary. The requirements may also vary depending on various clinical parameters such as therapeutic index, the type and number of indications for which SEB sponsors apply.

Proposed clinical indications for SEBs should be identical to or within the scope of the indications granted to the reference biologic drug. Clinical studies should be provided for each indication being sought. In some cases, comparative pharmacokinetic/pharmacodynamic (PK/PD) data to bridge two or more indications may be sufficient. If extrapolation of results from clinical studies for one indication to one or more different indications can be justified based on

• mechanism of action,
• pathophysiological mechanism of the diseases or conditions involved, and
• clinical experiences of the reference biologic drug,

a detailed scientific rationale that appropriately addresses the benefit/risk of such a proposal, should be provided to adequately support the data extrapolation.

The reference biologic drug should be the same for the C&M studies as compared to the reference product used in the non-clinical and clinical studies. Additionally the SEB product used in the non-clinical and clinical studies should the same as that which is market authorization is sought. In some instances, C&M changes introduced during in the clinical development phase, or at the end of the clinical development programme, should be bridged by additional PK/PD data and/or clinical data. Should this be the case, sponsors are advised to consult with BGTD for additional guidance.

2.3.2.2 Non-clinical studies

Non-clinical studies should be conducted prior to the initiation of any clinical studies. These studies should be comparative and designed to detect significant differences between the SEB and the reference biologic drug.

2.3.2.3 Clinical studies

Pharmacokinetic studies
Comparative pharmacokinetic studies should be conducted to demonstrate the similarities in PK characteristics between the SEB and the reference biologic drug.

The designs of comparative bioavailability studies (e.g., single-dose study versus multiple-dose study, or cross-over versus parallel study) should take the following factors into considerations:

• half-life,
• linearity of PK parameters,
• where applicable, the endogenous level and diurnal variations of the protein under study,
• production of neutralizing antibodies,
• conditions and diseases to be treated, and
• indications for which the SEB sponsor is applying.

Results from healthy subjects may not adequately reflect the PK parameters in the patient population where the product is indicated. Therefore, it is best to conduct the studies in the relevant patient population. However, where it is justifiable, PK studies may be conducted in healthy subjects. Dose(s) used in the PK studies should be within the therapeutic dosing range specified in the Product Monograph (PM) of the reference biologic drug.

The principles of study design and statistical methods outlined in the "Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A Oral Dosage Formulations Used for Systemic Effects (1992)(Guideline A)" should be used as a general guidance for comparing and analysing similarity of the PKs between the SEB and the reference biologic drug. PK parameters should not be limited to parameters reflecting absorption only. Differences in elimination (clearance and terminal half-life) should also be compared. Data should not be excluded from the analysis unless it can be justified and considered to be acceptable.  

Acceptable criteria for the determination of similarity in comparative pharmacokinetics between the SEB and the reference biologic drug should be defined prior to the initiation of PK studies, taking into consideration known PK parameters and their variations, assay methodologies, and the safety and efficacy of the reference biologic drug and SEB. Meeting criteria for the comparative bioavailability studies for generic pharmaceuticals, outlined in Guideline A² is desirable and is generally achievable in comparative PK studies of SEBs. When such criteria are not met, a discussion should be provided regarding the implication of the findings of clinical efficacy in conjunction with the efficacy data obtained from the comparative clinical trials.

Pharmacodynamic studies
The parameters investigated in PD studies should be clinically relevant and surrogate markers should be clinically validated. PD studies may be combined with PK studies, in which case the PK/PD relationship should be characterized. As for all other studies in the SEB developmental programme, the PD studies should be comparative in nature.

Clinical efficacy and safety trials
Comparative clinical trials are required to demonstrate the similarity in efficacy and safety profiles between the SEB and the reference biologic drug. The design of the studies and the clinical comparability margins are important and should be given careful consideration and justified on clinical grounds.

The nature, severity, and frequency of adverse events shall be compared between the SEB and the reference biologic drug, and be based on safety data from a sufficient number of patients treated for an acceptable period of time. Efforts should be made to ensure that comparative clinical studies have the statistical power to detect significant differences in safety between the SEB and the reference biologic drug.

The immunogenicity of the SEB shall be evaluated using appropriately designed clinical studies with state of art methods from both efficacy and safety perspectives.

A written rationale on the strategy for testing immunogenicity should be provided. Assay methods should be validated and be able to characterize antibody content (concentration or titre), and the type of antibodies formed. Antibodies that have a potential serious impact on safety and efficacy, such as neutralizing antibodies and antibodies with cross-reactivity, are of concern.

When neutralizing antibodies are detected in patients in clinical trials, the impact of the antibodies on the PK/PD parameters of the SEB should be analyzed. Furthermore, an assessment of the impact of the neutralizing antibodies and cross-reacting antibodies (if applicable) on the overall efficacy and safety of the SEB should be conducted. Should there be cause for concern, the duration of the clinical trials should be extended in order to obtain longer-term safety and efficacy data prior to authorization. In some cases, a more detailed pharmacovigilance plan and Risk Management Plan, may need to be implemented in the post-market phase.

2.3.3 Risk Management Plan (RMP)

An SEB is not the first in its class to be brought to market, however, it will be authorized based on a reduced non-clinical and clinical data package due to reliance on information from a reference biologic drug. Given the uncertainty in the risks of an SEB, it is important that a risk management plan be presented prior to issuance of marketing authorization. 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 SEB.
  
The RMP for the reference biologic drug should also be utilized in the development of the RMP for the SEB. The minimum criteria for surveillance for each SEB product should be described in accordance with the requirements for a new biologic drug. The RMP should include detailed information of a systematic evaluation of the immunogenicity potential of the SEB.  A discussion about methods to distinguish adverse event reports from the similar licensed products, including the reference product should be included in the RMP. The RMP should be maintained and implemented throughout the life-cycle of the product.

2.3.3.1 Pharmacovigilance Plan (PvP)

A PvP should be provided and should include the submission of periodic safety update reports (PSURs). The PSURs for an SEB should include a discussion of the benefit/risk of the SEB post-market.

2.4 Post-Market Requirements

2.4.1  Adverse Drug Reaction (ADR) Reporting

ADR reporting is required post-market under section C.01.016 of the Food and Drug Regulations: any serious ADR that is reported requires the manufacturer of that drug to submit all information with respect to that report within 15 days after receiving the information.  Furthermore, on an annual basis or as requested by the Director, the manufacturer will conduct a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions after such an occurrence. After an analysis, the Director may request written summary reports where safety is questionable.

At any time after an NOC is issued, the authority to suspend such an authorization is set out in C.08.006 of the Food and Drug Regulations.  The Minister may, by notice to a manufacturer, suspend for a definite or indefinite period, a NOC issued to that manufacturer in respect of an NDS if the Minister considers that the drug is not safe for the use represented in the submission, as shown by evidence obtained from clinical or other experience or tests by new methods.

2.4.2 Periodic Safety Update Reports (PSURs)

PSURs should be submitted as discussed in the PvP. The periodicity for submission of PSURs shall be consistent with ICH guidelines (ICH E2E) for new products or as determined by the Minister on approval.  

2.5 Labelling requirements (Product Monograph)

Unlike generic pharmaceutical drugs, the sponsor of an SEB will not be able to utilize the PM of the reference biologic drug in its entirety as that of its own product. The PM for an SEB should be developed in a manner consistent with the principles, practices, and processes outlined in the "Guidance for Industry: Product Monograph (2004)". The contents of the PM for SEBs will include key following information:

• Key data on which the decision for market authorization was made.
• Tables showing the results of the comparisons between the SEB and reference biologic drug
• Information on the indications approved for use.
• There should be no claims for bioequivalence between the SEB and reference biologic drug
• There should be no claims for clinical equivalence between the SEB and the reference biologic drug.

The Notice of Decision and Summary Basis of Decision of an SEB will be published.

2.6 Harmonization with other international regulators

It is Health Canada's intention to harmonize as much as possible with other competent regulators and international organizations such as the World Health Organization (WHO) and the ICH. Hence, Health Canada will be adapting suitable definitions, terminology, and applicable guidance documents.

References

1. Health Canada (2008) Draft Guidance Document:  Data Protection under C.08.004.1 of   the Food and Drugs Regulations
   
   
2. Health Canada (2007) Draft Guidance Document: Patented Medicines (Notice of Compliance) Regulations
   
   
3. Health Canada (1992) Guideline :  Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A Oral Dosage Formulations Used Systematic Effects
   
   
4. ICH Q1A (R2): Stability Testing of New Drug Substances and Products (Second Revision)
   
   
5. ICH Q2A: Validation of Analytical Procedures: Text and Methodology
   
   
6. ICH Q2B: Validation of Analytical Procedures: Methodology
   
   
7. ICH Q5C: Quality of Biotechnological Products:  Stability Testing of Biotechnological/ Biological Products
   
   
8. ICH Q5E: Comparability of Biotechnology/Biological Products Subject to Changes in their Manufacturing Process.
   
   
9. ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products

¹ No person shall sell or advertise a new drug unless, the manufacturer has filed to the Minister a New Drug Submission. Food and Drug Regulations C.08.002 (1)
A New Drug Submission shall contain sufficient information to assess the safety and effectiveness of a new drug Food and Drug Regulations C.08.002 (2)

² The following bioequivalence standards are outlined in Guideline A:
a) The 90% confidence interval of the relative mean AUCT of the test to reference product should be within 80 percent to 125 percent, and
b) The relative mean measured Cmax of the test to reference product should be between 80 percent and 125 percent.
These standards must be met on log transformed parameters calculated from

• the measured data, and
• data corrected for measured drug content (percent potency of label claim).

These bioequivalence standards may not be applicable to all biologics.