SEB submissions in Canada

Presented by
Neha Gandhi
Yogender Arya

1

Bio-therapeutic products also known as biologic drugs have a
successful record in treating many life-threatening and chronic
diseases.

The recent expiration of patents and/or data protection for the first
major group of originator biologics and the anticipation of additional
expirations has led to the development of products that are designed
to be “similar” to a licensed originator product.

In Canada, they are referred to as Subsequent Entry Biologics (SEBs),
copies of previously approved biological products.

By Yogendra Arya and Neha Gandhi 2

Biologics SEBs
Biologics are drug products derived SEB is defined by Health Canada as
from biological sources and include “a biologic drug that enters the
gene therapies, vaccines, antibodies market subsequent to a version
and other therapeutic products previously authorized in Canada, and
derived through biotechnology with demonstrated similarity to a
reference biologic drug.
In order for a product to be considered an SEB it should have the same
therapeutic effects as the originally approved biologic, a similar safety profile
and the same guarantees to be free of contaminating viruses or other
infectious agents.
SEB manufacturers may make reference to the information contained in an
innovator’s biologic drug submission – that is, the reference biologic drug
submission – in order to reduce the amount of clinical data required to obtain
marketing approval for its product.


The Biologics and Genetic Therapies Directorate (BGTD) regulates biologics
under Divisions 1, 1A, 2, 4, 5, and 8 of Part C of the Food and Drug
Regulations.

Information provided by manufacturers is evaluated to verify that the
biologic meets quality, safety and efficacy requirements, and that the benefits
of the biologic outweigh the risks for its intended use.

A Notice of Compliance (NOC) and Drug Identification Number (DIN) are
issued to sponsors when their products are authorized for sale (distribution)
in Canada.

After a biologic has received an NOC, the manufacturer must adhere to
BGTD's Lot Release Program, which sets out risk-based criteria for testing of
the product prior to its release onto the Canadian market.


EXAMPLES OF BIOLOGIC DRUGS AND THEIR USES

DRUG THERAPEUTIC FOCUS

Hormone Product, Growth Hormone, Growth Hormone Disorder, Anemia Associated With Kidney Disease,
Erythropoietin, Insulin Diabetes

Immuno modulator Interferon-Beta-1b Multiple Sclerosis

Monoclonal Antibodies: Infliximab, Inflammatory Disorders: Rheumatoid Arthritis, Cancer, Macular
Adalimumab, Trastazumab Ranzibizumab, Degeneration, Non-Hodgkin’s Lymphoma, Lumphocytic, Leukemia,
Rituximab Rheumatoid Arthritis

Enzymes Imiglucerase Gaucher Disease
Anti-coagulant therapy low molecular weight
heparin Clotting Disorders

The concept of an SEB applies to all biologic drug submissions where the
sponsor seeks authorization for sale based on demonstrated similarity to a
previously approved biologic drug.

Existence of Reference Biological Drug
 authorized for sale
 sufficient efficacy and safety data

The product (i.e., SEB) can be well characterized by a set of modern analytical
methods

The SEB, through extensive characterization and analysis, can be judged
similar to the reference biologic drug by meeting an appropriate set of pre-
determined criteria.

It applies 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 responsibility of sponsor to provide the necessary evidence to support the
application

 The Food and Drugs Act and Regulations within the existing regulatory
frameworks for biologic, pharmaceutical, and generic pharmaceutical drugs

 Similarity between the SEB and Reference

 Authorization of an SEB is not a declaration of pharmaceutical or therapeutic
equivalence to the reference biologic drug.

 All SEBs are subject to the laws, and patent and intellectual property principles
outlined within the Food and Drug Regulations (Data Protection), Patented
Medicines (Notice of Compliance) Regulations, and the Patent Act.

 Once a Notice of Compliance (NOC) is issued, the SEB is a new biologic drug and
regulated accordingly. However, an SEB should not be used as a reference
biologic drug for another SEB submission.


Applicable Regulations: Subject to the Food and Drug
Regulations for authorization and oversight for the following:

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.

C.08.002 (2): A New Drug Submission shall contain sufficient
information and material to enable the Minister to assess the
safety and efficacy of a new drug.


Reference Biologic Drug

 Suitable to support the submission;
 Authorized for sale and should be marketed in Canada;
 The same reference biologic drug should be used throughout
the studies supporting the safety, quality, and efficacy of the
product
 Same dosage form, strength, and route of administration
 The active substance must be shown similar;
 An SEB should not be used as a reference biologic drug; and
 Should have adequate safety, efficacy, and effectiveness data


Regulated by Part C, Division 8 of the Food and Drug.

Submission requirements for SEBs will be determined on a case
by case basis, and may
include, but not be limited to:

 A complete chemistry and manufacturing data package
 A rationale for the choice of the innovator biologic and
extensive published information on its safety and efficacy.
 Sufficient characterization information to demonstrate both
chemical and biological comparability to the innovator
product.
 Sufficient comparative animal toxicity and toxicological
data, where appropriate.


 Pharmacodynamic data to demonstrate comparable
bioactivity based on parameters or surrogate markers that
are clinically relevant and validated.
 Pharmacokinetic data to demonstrate comparable
bioavailability of the SEB to the innovator product based on
suitable validated pharmacokinetic parameters.
 Data characterizing the immunogenic profile of the SEB in
humans and its potential impact on safety and efficacy.
 A clinical package which demonstrates the safety and
efficacy of the SEB including comparative studies between
the SEB and innovator products


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.

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

If a non-Canadian reference biologic drug is used in clinical
studies in Canada, data must be provided to support its safety
and to satisfy the intent of the regulatory requirements for
chemistry and manufacturing information. .


The target time for review of an SEB will be the
same as that for an NDS.

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


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 characterization Studies
conducted in a side-by-side format.


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 containing
appropriate cross-references.

However, the reorganization of modules 2 and 3 of a
CTD submission already prepared for another
regulatory jurisdiction should not be necessary


Once granted an 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.


An SEB product sponsor is eligible to apply for one or more clinical
indications granted to the reference biologic drug in Canada.

Where a clinical indication being sought is not held by the reference
biological drug, full clinical trial data shall be provided in support of
that indication.

Non-clinical studies:
In vitro studies
In vivo studies

Clinical studies:
Pharmacokinetic studies
Pharmacodynamic studies
Clinical efficacy and safety trials


An SEB is not the first in its class to be brought to
market; it is therefore important that an RMP 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.


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 balance of the
SEB post-market.


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.


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 contents of the PM for SEBs will include following information:

 A statement indicating that the product is an SEB

 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


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. Hence,
Health Canada may be adapting suitable definitions,
terminology, and applicable guidance documents.

Health Canada recommends that sponsors refer to the product
class specific guidance documents developed by the Similar
Biological (Biosimilar) Medicinal Products Working Party,
European Medicines Agency as the scientific principles are
consistent with those of Health Canada.


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

 http://www.hc-sc.gc.ca/dhp mps/alt_formats/pdf/brgtherap/
applic-demande/guides/seb-pbu/seb-pbu-2010-eng.pdf


SEB submissions in Canada

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