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
12345-
Introduction
Fundamental Concepts and Principles
Data Requirements
Reference product
Conclusions
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Health Products and Food Branch
1-
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
2-
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
3-
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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