Transcript Slide 1
gust 22, 2007
Helping the people
of Canada maintain and
improve their health
Aider les Canadiens et
les Canadiennes à maintenir
et à améliorer leur santé
Regulatory approach and consideration for
Subsequent Entry Biologics (SEBs) in Canada
Agnes V. Klein, MD DPH
Biologics and Genetic Therapies Directorate
Health Canada
April, 2010
Health Products and Food Branch
Topics for Discussion
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Introduction
Fundamental Concepts and Principles
Data Requirements
Reference product
Conclusions
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Health Products and Food Branch
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Introductions
Health Canada’s mission is to help Canadians maintain and
improve their health
The mandate of the Health Products and Food Branch is to
take an integrated approach to the management of the risks
and benefits to health-related products and food by:
Minimizing health risk factors to Canadians while maximizing the
safety provided by the regulatory system for health products and
food; and
Promoting conditions that enable Canadians to make health choices
and providing information so that they can me informed decisions
about their health
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Health Products and Food Branch
Drivers for SEBs
Expiry of patents for biologics
Public demand for affordable products
Change in global market dynamcs for
biologic drugs
Submissions for SEBs and enquiries for filing
of SEBs
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Health Products and Food Branch
Canadian Regulatory Context
Changing regulatory environment
Lifecycle approach (Progressive Licensing
Framework/Project)
Increase in “best practices” approach;
Regulated Marketplace, but:
Smaller in size than USA and Europe
Not primary target for SEB development and
submissions
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Health Products and Food Branch
Differences: Biologics vs Pharmaceuticals
Biologic Drugs
Derived from living organisms
Relatively large in size
Pharmaceutical Drugs
Derived from chemical sources:
mostly by synthesis
Relatively small in size (called
small molecules)
Highly variable
Regulatory oversight on process
of product
Minimally variable
Regulatory oversight on finished
product
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Health Products and Food Branch
Challenges for SEBs
Unpredictable immunogenicity of biologics
Most biologics induce antibodies
Manufacturing changes can cause unexpected changes
Analytical methods can not fully predict biological
properties
Immunogenicity can have serious consequences
Hence need for enhanced post-market
surveillance for all new biologics, including SEBs
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Health Products and Food Branch
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Fundamental Concepts and underlying
Principles
The information and submission requirements for
authorization of SEBs outlined in the guidance document
should permit a sponsor to satisfy the requirements of the
Food and Drug Regulations
A New Drug Submission shall contain sufficient information to assess
the safety and effectiveness of a new drug including…C.08.002(2)
The onus is on the sponsor to provide the necessary
evidence to support all aspects of an application for market
authorization
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Health Products and Food Branch
Fundamental Concepts and underlying Principles
Regulatory decisions on SEBs will be based on
scientific and regulatory principles that are in the
Food and Drugs Act and Regulations
The principles within the existing regulatory
frameworks for biologics, pharmaceuticals and
generic pharmaceutical drugs are used as the
bases for the regulatory framework for SEBs
The basis for a product being authorized as an SEB
hinges on the ability to demonstrate similarity to a
suitable reference biologic product
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Health Products and Food Branch
Fundamental Concepts and underlying Principles
SEBs are not “generic biologics” and many characteristics
associated with 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
Once a Notice of Compliance (NOC) is granted, the SEB is a
new biologic drugs and is regulated like any other new
biologic drug. However, and SEB can not be used as a
reference biologic product
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Health Products and Food Branch
Fundamental Concepts and underlying Principles
An SEB will only be authorized based on a submission that makes either a
direct comparison to an innovator product previously authorized for sale in
Canada. All the laws, patent and intellectual property principles outlined in
the Food and Drug Regulations (Data Protection) and Patented Medicines
(Notice of Compliance) Regulations are applicable to SEBs
Subsequent manufacturer approval on the basis of direct or indirect
comparison with the “innovator drug” is prohibited until 8 years after
authorization of the innovator drug
6 year “no-filing period” drug in which SEB sponsors are prohibited from filing
a submission that compares directly or indirectly with the innovative drug
6 months paediatric exclusivity
NOTE: In some circumstances a biologic product (must be named) that is
not marketed in Canada may be used as a reference. The biologic must
be named and it is preferred that it be used in the comparative studies.
The guidance document should be consulted
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Health Products and Food Branch
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Data Requirements
Chemistry/Manufacturing
Drug Substance
Manufacture
Characterization
Control
Ref. standard
Container
Stability
Facility Information
Drug Product
Description
Development
Manufacture
Control
Ref. standard
Container
Stability
Facilty Information
Non-clinical
Pharmacology
•Primary activity
•Secondary activity
•Safety pharmacology
•Interactions
Clinical
Pharmacology
Pharmacokinetics
•Single dose
•Repeat dose
•Special populations
Pharmacokinetics
Efficacy and Safety
•ADME
•Interactions
•Dose finding
•Schedule finding
•Pivotal
Toxicology
•Single dose
•Repeat dose
•Genotoxicity
•Carcinogenicity
•Reproduction
•Local tolerance
•Indication1
•Indication 2, etc
Immunogenicity
Post-market PvP, RMPs,
etc.
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Health Products and Food Branch
Quality
Full Chemistry and Manufacturing package
Extensive data on the demonstration of similarity with the reference
biologic drug including
Characterization studies side by side
Studies should be comprehensive and well rationalized to allow deduction of
similarity
Formulated drug product may be feasible to undertake comparability
Comparison of drug substance may be beneficial or the only scientific
option; additional studies should demonstrate that the drug substance is
not changed
Comparison of SEB drug product and SEB isolated drug substance may
be helpful
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Health Products and Food Branch
Quality
Comparability exercise: Considerations
Same principle and approaches as in ICH Q5E are applicable
Purpose to ascertain whether SEB and chose reference can be
judged highly similar in terms of quality attributes allowing to support
conclusions of similarity for safety and efficacy
Extent of studies will depend on:
Nature of the product
Availability of suitable analytical techniques to detect differences
Relationship between quality attributes and safety and efficacy, based
on overall non-clinical and clinical experience
The following should be evaluated, for ex: physicochemical and
biological characterization, analyses from different stages of
process, stability data, multiple batches to characterize variability
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Health Products and Food Branch
Quality
Determine critical control points, adequacy of in-process controls, type
and extent of data to be derived from non-clinical studies
Analytical techniques
Select carefully and optimize
Depends on the reference biologic drug chosen
Assays should be scientifically sound and provide reliable results
Characterization
Use appropriate techniques as per ICHQ6B including
Characterization of physicochemical properties
Biological Activity
Immunochemical properties, purity, impurities, contaminants and
quantity
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Health Products and Food Branch
Quality
Complete side by side characterization
Additional characterization may be needed
Physicochemical properties
According to ICHQ6B
Biological Activity
Limitations of biological assays should be considered (e.g. high
variability)
Can confirm that change in structure has not occurred
When not adequate, data from non-clinical or clinical studies may
be supportive
If reliance is too high, the procudt may not be suitable as a SEB
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Health Products and Food Branch
Quality
Immunochemical properties
Specifications
Stability (ICHQ5C and Q1A(R)
Manufacturing process considerations
Determination of similarity
Signifies that the quality attributes of the two products are highly
similar (not identical)
Non-Clinical and clinical data previously generated with the
reference product are relevant to the SEB
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Health Products and Food Branch
Quality
Analytical procedures are not sufficient to discern
relevant differences
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
Data should be organized as per CTD
Once grand an NOC, an SEB becomes a standalone product
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Health Products and Food Branch
Non-Clinical and Clinical Information
Apply to SEBs that have demonstrated to be similar to the
reference product chosen
Only general guidance is provided
One or more indications may be applied for, based on the
product chosen for reference
Proposals for additional indications of the reference product
may be granted to the SEB; PK/PD may be sufficient for
extrapolation; extrapolation may also be possible based on
pathophysiological mechanisms; scientific rationale is
required
The reference biologic should the same for all studies
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Health Products and Food Branch
Non-Clinical and Clinical Information
Non-clinical studies
According to principles in ICH S6; comparative and
designed to detect significant differences between the
SEB and the reference biologic
In vitro: receptor binding or cell-based assay, as/when
appropriate
In vivo: relevant PD studies; at least one repeat toxicity study;
sufficient duration to detect differences in toxicity and/or
immune responses; local tolerance. All studies can be
concurrent, as part of one study
Other toxicological studies, safety pharmacology, reproductive
toxicity; mutagenicity and carcinogenicity – not required, unless
warranted by the results of the repeat-dose toxicological studies
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Health Products and Food Branch
Clinical Studies
Pharmacokinetic studies
Comparative PK studies should consider the following:
T/2 of the biologic
Linearity of PK parameters
Endogenous levels/diurnal variation where applicable
Diseases/Conditions to be treated
Route (s) of administration
Indication (s) being applied for
Use volunteers, but most likely patient population
Use doses for studies, within the therapeutic range of the reference as
specified in PM
Use general principles of study design and statistical methods
Clearance times should be compared
Exclude data only if acceptable to Health Canada-BGTD
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Health Products and Food Branch
Clinical Studies
Acceptable criteria should be defined in advance, for similarity taking
into consideration known PK parameters and their variations, assay
methodologies, all available safety and efficacy of the reference
biologic
Consider criteria used for bioavailability studies of generic
pharmaceuticals; when not met, implications of findings should be
discussed
Pharmacodynamic studies
Parameters should be clinically relevant
Surrogates should be clinical validated
PD studies may be combine with PK studies; PK/PD relationship
should be characterized; PD studies should be comparative in nature
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Health Products and Food Branch
Clinical Studies
Clinical efficacy and Safety Trials
Conducted to demonstrate the similarity in safety and efficacy between
SEB and the reference biologic with a few exceptions: e.g. Insulin for
which only comparative safety is needed
Equivalence trials are generally preferred
Design of studies and comparability margins as well as primary
endpoints should be given careful consideration
Non-inferiority trials are considered but must be justified as they could
suggest superiority of the SEB, and this needs to be assessed for
relevance, including impact on safety. If confirmed, the product can no
longer be considered as an SEB
Extrapolation from non-inferiority studies to other indications might not
provide support for extrapolation
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Health Products and Food Branch
Clinical Studies
Nature, severity and frequency of AEs should be compared:
numbers should be sufficient and study of sufficient duration, to
allow this to happen
Immunogenicity should be evaluated in the clinical trials or specific
studies with state of the art methods: rationale for strategy should
be provided
Clinical Safety and Efficacy
Impact of neutralizing and cross-reacting antibodies, when detected,
on PK/PD parameters should be analyzed and their impact
assesses
Duration of studies may have to be extended in such event
Detailed PvP and RMP may need to be implemented
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Health Products and Food Branch
Clinical Studies
Post-market activities
SEBs reach market base on reduced non-clinical and clinical
package: therefore, RMP is important
Include methods to distinguish AEs from those for other products,
including the reference product
The RMP may be implemented and maintained throughout the
lifecycle of the product
PvP: should be provided with PSURs to include a discussion the
benefit-risk balance of the SEB post-market
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Health Products and Food Branch
Clinical Studies
Other Post-Market Requirements
Adverse Drug Reaction (ADR) reporting: as per C01.016; should be
reported as per the regulations within 15 days of receipt
Analyses may be conducted on request, with additional analyses as
needed
PSUR’s: should be submitted as discussed in the PvP, following ICH
E2E as noted at time of NOC
C.08.006 defines the authority for suspend the NOC (marketing of a
drug)
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Health Products and Food Branch
Labelling requirements
Canadian Label is the Product Monograph (PM)
Unlike generics, the pm of the reference product can only be
used practically
Requirements:
Indicating that product is and SEB
Key data on which decision to allow marketing has been mad
Information on the indications approved for use
No claims of bioequivalence can be made
No claims for clinical equivalence can be made
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Health Products and Food Branch
Role of reference product
Additional non-clinical and clinical data are obtained from publicly
available information the Reference Product to support the authorization
of the SEB
Reference biologic product is therefore critical to the authorization of
SEBs
The Reference Product is not the sole source of no-clinical and clinical
information
For generics, the reference product or national comparator determines the
use and/or of the generic as a substitute; extrapolation to available
supportive clinical data in order to reduce unnecessary patient enrolment
The choice/use of RBP is not to precisely indicate the marketed product
for which the SEB can be substituted
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Health Products and Food Branch
Role of reference product
Authorization of an SEB will be based on a less extensive clinicl data
package (i.e. reduced number and/or size of clinical trials)
Data from Reference Product must be of high quality
SEB must be demonstrated to be similar to the reference product
Comparability Exercise (quality component) does not provide complete
information required for the decision to authorize
The reference biologic product should be authorized and marketed in
Canada
The active substance of reference product should have significant safety
and efficacy data accumulated such that the demonstration of similarity
will bring into relevance a substantial body of reliable data
Where a non-Canadian Reference Product is contemplated, the sponsor
should contact Health Canada early in the development process.
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Health Products and Food Branch
Role of reference product
Use of non-Canadian reference product
Non-Canadian reference product
From jurisdictions with an established relationship with
HPFB is preferred
Widely marketed in a jurisdiction that adopts ICH
guidelines and with regulations and principles of
evaluation, post-market surveillance, and approach to
comparability similar to Canada
The submission includes sufficient information to explain
explicitly the link between the Reference Product and the
same innovative product approved in Canada
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Health Products and Food Branch
Indications and Substitutability
Indications granted shall be based on data provided by the
sponsor
If the SEB sponsor does not provide data to support all the
indications of the reference product, the SEB will not automatically be
granted all the indications of the RBP
Indications not held by the reference biologic product will
require supportive clinical trial data
SEBs should be eligible to apply for indication (s) within
those granted to the reference biologic product
Interchangeability (Substitutability) remains a Provincial
decision in Canada
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Health Products and Food Branch
Conclusions
SEBs will be part of the high quality, safe and effective
biologic drugs available to Canadians
SEBs are “stand alone” and not “generic” versions of the RBP
SEBs can be equated to innovator biologic drugs
SEBs are not automatically substitutable and may not have all
indications of reference products
Health Canada intends to harmonize as much as possible
with other competent regulators and international
organizations such as the WHO, as much as possible
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Health Products and Food Branch
Conclusions
HC may adapt definitions, terminology
and applicable guidance, in the future
HC recommends that sponsors refer to
class-specific guidance of the EMEA,
as the scientific principles are
consistent with those in Canada
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Health Products and Food Branch
Thank you
?
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