Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Considerations in
Demonstrating
Interchangeability With
a Reference Product
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2019
Biosimilars

Considerations in
Demonstrating
Interchangeability With a
Reference Product
Guidance for Industry
Additional copies are available from:
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Center for Drug Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
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Food and Drug Administration
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Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2019
Biosimilars

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	SCOPE ............................................................................................................................... 2
IV. 	GENERAL PRINCIPLES ............................................................................................... 3
V. 	FACTORS IMPACTING THE TYPE AND AMOUNT OF DATA AND
INFORMATION NEEDED TO SUPPORT A DEMONSTRATION OF
INTERCHANGEABILITY ......................................................................................................... 5
A. 	Product-Dependent Factors That May Impact the Data Needed to Support a Demonstration
of Interchangeability ...................................................................................................................... 6
1. Product Complexity and the Extent of Comparative and Functional Characterization .................. 6
2. Product-Specific Immunogenicity Risk ............................................................................................ 7
3. Totality of Factors to Consider in Assessing the Data and Information Needed to Support a
Demonstration of Interchangeability ................................................................................................... 7
B. 	Biosimilar Product Postmarketing Data That May Impact the Data Needed to Support a
Demonstration of Interchangeability ............................................................................................ 8
VI. 	DATA AND INFORMATION NEEDED TO SUPPORT A DEMONSTRATION OF
INTERCHANGEABILITY ......................................................................................................... 9
A. 	Considerations for the Design and Analysis of a Switching Study or Studies Needed to
Support a Demonstration of Interchangeability .......................................................................... 9
1. Study Endpoints ............................................................................................................................. 10
2. Study Design and Analysis ............................................................................................................. 11
3. Study Population............................................................................................................................ 13
4. Condition(s) of Use to Be Studied.................................................................................................. 14
5. Route of Administration ................................................................................................................. 14
B. 	Extrapolation of Data ................................................................................................................... 14
VII. 	CONSIDERATIONS REGARDING THE COMPARATOR PRODUCT IN A
SWITCHING STUDY OR STUDIES....................................................................................... 16
VIII. 	CONSIDERATIONS FOR DEVELOPING PRESENTATIONS FOR PROPOSED
INTERCHANGEABLE PRODUCTS ...................................................................................... 17
IX. 	POSTMARKETING SAFETY MONITORING CONSIDERATIONS .................... 18
ATTACHMENT I....................................................................................................................... 20

Contains Nonbinding Recommendations
Considerations in Demonstrating Interchangeability
With a Reference Product
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
This guidance is intended to assist sponsors in demonstrating that a proposed therapeutic protein
product is interchangeable with a reference product for the purposes of submitting a marketing
application or supplement under section 351(k) of the Public Health Service Act (PHS Act) (42
U.S.C. 262(k)). The Biologics Price Competition and Innovation Act of 2009 (BPCI Act)
amends the PHS Act and other statutes to create an abbreviated licensure pathway in section
351(k) of the PHS Act for biological products shown to be biosimilar2 to or interchangeable with
an FDA-licensed biological reference product3 (see sections 7001 through 7003 of the Patient
Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148)). Although the
351(k) pathway applies generally to biological products, this guidance focuses on therapeutic
protein products and gives an overview of important scientific considerations in demonstrating
interchangeability of a proposed therapeutic protein product (proposed interchangeable
biosimilar4 or proposed interchangeable product) with a reference product.
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration.
2 Section 351(i)(2) of the PHS Act defines biosimilar or biosimilarity to mean that “the biological product is highly
similar to the reference product notwithstanding minor differences in clinically inactive components” (highly similar
provision) and that “there are no clinically meaningful differences between the biological product and the reference
product in terms of the safety, purity, and potency of the product” (no clinically meaningful differences provision).
3 Section 351(i)(4) defines reference product to mean “the single biological product licensed under subsection (a)
against which a biological product is evaluated in an application submitted under subsection (k).”
4 In this guidance, the following terms are used to describe biological products licensed under section 351(k) of the
PHS Act: (1) “biosimilar” or “biosimilar product” refers to a product that FDA has determined to be biosimilar to
the reference product (see sections 351(i)(2) and 351(k)(2) of the PHS Act) and (2) “interchangeable biosimilar” or
“interchangeable product” refers to a biosimilar product that FDA has determined to be interchangeable with the
reference product (see sections 351(i)(3) and 351(k)(4) of the PHS Act).
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This guidance is one in a series of guidances that FDA is developing to implement the BPCI Act
and includes references to information from other FDA guidances, where appropriate.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
Section 351(k) of the PHS Act, as amended by the BPCI Act, sets forth the requirements for an
application for a proposed biosimilar product and an application or a supplement for a proposed
interchangeable product. Section 351(k)(4) of the PHS Act further provides that upon review of
an application submitted under section 351(k) or any supplement to such application, FDA will
determine the biological product to be interchangeable with the reference product if FDA
determines that the information submitted in the application or the supplement is sufficient to
show that the biological product “is biosimilar to the reference product” and “can be expected to
produce the same clinical result as the reference product in any given patient”5 and that “for a
biological product that is administered more than once to an individual, the risk in terms of
safety or diminished efficacy of alternating or switching between use of the biological product
and the reference product is not greater than the risk of using the reference product without such
alternation or switch.”6
Section 351(i) of the PHS Act states that the term interchangeable or interchangeability, in
reference to a biological product that is shown to meet the standards described in section
351(k)(4) of the PHS Act, means that “the biological product may be substituted for the
reference product without the intervention of the health care provider who prescribed the
reference product.”7
III. 	SCOPE
This guidance provides an overview of important scientific considerations in demonstrating
interchangeability with a reference product, including the following:
 	Data and information needed to support a demonstration of interchangeability
5 Section 351(k)(4)(A) of the PHS Act.
6 Section 351(k)(4)(B) of the PHS Act.
7 The terms interchangeable or interchangeability in this guidance have the same meaning as defined in section
351(i)(3) of the PHS Act.
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 	Considerations for the design and analysis of a switching study or studies to support a
demonstration of interchangeability
 	Considerations regarding the comparator product in a switching study or studies
 	Abbreviated considerations for developing presentations, container closure systems, and
delivery device constituent parts for proposed interchangeable products8,9
IV. 	GENERAL PRINCIPLES
FDA intends to consider the totality of the evidence provided by a sponsor when the Agency
evaluates the sponsor’s demonstration of interchangeability according to the criteria set forth in
section 351(k).
To support a demonstration of interchangeability, section 351(k)(4)(A) of the PHS Act provides,
among other things, that a sponsor must show that the proposed interchangeable product “is
biosimilar to the reference product.” Where a product is first licensed as a biosimilar, that
licensure may be referenced to support a showing for this statutory criterion for demonstrating
interchangeability.
In addition, section 351(k)(4)(A) of the PHS Act provides that an application for an
interchangeable product must include information sufficient to show that the proposed
interchangeable product “can be expected to produce the same clinical result as the reference
product in any given patient.” FDA expects that sponsors will submit data and information to
support a showing that the proposed interchangeable product can be expected to produce the
same clinical result as the reference product in all of the reference product’s licensed conditions
of use.
8 Products that include both a biological product and a device constituent part to deliver the biological product are
combination products (see 21 CFR parts 3 and 4). For example, the delivery device constituent part and the
biological product constituent part may be a single entity (e.g., a prefilled syringe) or the two constituent parts may
be co-packaged (e.g., a biologic in a vial packaged in the same box with a syringe). The primary mode of action of
these combination products is provided by the biological product constituent part, which is regulated by CDER or
CBER. CDER or CBER, therefore, will have primary jurisdiction for these combination products; and these Centers
and the Center for Devices and Radiological Health (CDRH) will coordinate as appropriate.
9 Considerations specific to demonstrating interchangeability under section 351(k)(4) of the PHS Act with respect to
container closure systems and delivery device constituent parts are addressed in section VIII of this guidance. This
guidance does not address other information generally necessary to support the proposed container closure system
and/or the delivery device constituent part of a proposed interchangeable product. Sponsors should also refer to
relevant FDA guidance documents and resources from CBER, CDRH, CDER, and the Office of Combination
Products (OCP) to assess what other data and information should be included to support the proposed container
closure system(s) and/or delivery device constituent part(s). (Some of the FDA guidances and other resources that
address these topics are referenced at appropriate places in section VIII of this guidance.)
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The data and information necessary to meet the section 351(k)(4)(A) standard may vary
depending on the nature of the proposed interchangeable product10 and may include the
following:
 	The identification and analysis of the critical quality attributes11
 	The identification of analytical differences between the reference product and the
proposed interchangeable product, and, in addition, an analysis of the potential clinical
impact of the differences
 	An analysis of mechanism or mechanisms of action in each condition of use for which
the reference product is licensed, which may include the following:
- 	The target receptor or receptors for each relevant activity/function of the product
- 	The binding, dose/concentration response, and pattern of molecular signaling upon
engagement of target receptor or receptors
- 	The relationship between product structure and target/receptor interactions
- 	The location and expression of target receptor or receptors
 	An analysis of any differences in the expected pharmacokinetics and biodistribution of
the product in different patient populations for which the reference product is licensed
 	An analysis of any differences in the expected immunogenicity risk of the product in
different patient populations for which the reference product is licensed
 	An analysis of any differences in expected toxicities of the product in each condition of
use and patient population (including whether the expected toxicities are related to the
pharmacological activity of the product or to off-target activities) for which the reference
product is licensed
 	Information on any other factor that may affect the safety or efficacy of the product in
each condition of use and patient population for which the reference product is licensed
Where applicable, the data and information should include a scientific justification as to why any
differences that exist between the reference product and the proposed interchangeable product,
with respect to the factors described, do not preclude a showing that the proposed
interchangeable product can be expected to produce the same clinical result as the reference
product in any given patient. As previously noted, the data and information may vary depending
10 Some of this data and information may have been generated previously by the sponsor to support a demonstration
that the biological product is biosimilar to the reference product. If the applicant has previously submitted this data
or information to FDA, (e.g., in an application for a biosimilar product) the applicant should consult with FDA as to
how to reference or submit these data for purposes of seeking licensure as an interchangeable product.
11 Critical quality attributes include those attributes that define a product’s identity, quantity, safety, purity and
potency. See the ICH guidance for industry Q8(R2) Pharmaceutical Development (November 2009).
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on the nature of the proposed interchangeable product, and not all factors will necessarily be
relevant to a given scientific justification. The data and information may also include a scientific
rationale for extrapolation of data and information to support a demonstration of
interchangeability. Extrapolation is further described in section VI.B of this guidance.
Generally, the data and information to support a showing under the “can be expected to produce
the same clinical result as the reference product in any given patient” standard will likely not
involve additional clinical studies other than those necessary to support other elements of
demonstrating interchangeability, which are described in section VI. We note that although a
sponsor may seek licensure for a proposed interchangeable product for fewer than all conditions
of use for which the reference product is licensed, we recommend that a sponsor seek licensure
for all of the reference product’s licensed conditions of use when possible.
Further, for biological products administered more than once to a patient, section 351(k)(4)(B) of
the PHS Act provides that another of the criteria for FDA to make a determination of
interchangeability is a finding that information in the application is sufficient to show that “the
risk in terms of safety or diminished efficacy of alternating or switching between use of the
biological product and the reference product is not greater than the risk of using the reference
product without such alternation or switch.” FDA expects that applications generally will
include data from a switching study or studies12 in one or more appropriate conditions of use.
FDA anticipates that data and information acquired from a switching study or studies will be
useful in assessing the risk, in terms of safety and diminished efficacy, of alternating or
switching between the products. Considerations for the design of a switching study, including
study endpoints, study design and analysis, study population, condition(s) of use, and routes of
administration to be studied, are discussed in detail in section VI.A of this guidance.
V. 	FACTORS IMPACTING THE TYPE AND AMOUNT OF DATA AND
INFORMATION NEEDED TO SUPPORT A DEMONSTRATION OF
INTERCHANGEABILITY
The data and information needed to support a demonstration of interchangeability, beyond that
needed to demonstrate biosimilarity,13 may be dependent on and influenced by multiple factors,
which are discussed in this section.
12 The term switching study or studies as used throughout this guidance refers to a clinical study or studies used to
determine the impact of alternating or switching between the proposed interchangeable product and the reference
product.
13 Data and information needed to demonstrate biosimilarity are discussed in section VII of the guidance for industry
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015). We update
guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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A. 	Product-Dependent Factors That May Impact the Data Needed to Support a
Demonstration of Interchangeability
1. 	Product Complexity and the Extent of Comparative and Functional
Characterization
This section provides general, prospective considerations for evaluating the types and extent of
data needed to support a demonstration of interchangeability. These considerations may affect
the study design and aid in the justification of a development program for a proposed
interchangeable product. Consistent with the guidance for industry Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product (April 2015),14 the Agency recommends
that sponsors use a stepwise approach to generating data and information, which may allow the
sponsor to address any uncertainty about demonstrating interchangeability that may arise at each
stage of product development. At each stage, the sponsor should evaluate the extent to which
there is uncertainty about the interchangeability of the proposed product with the reference
product and identify a strategy to address that uncertainty.
Section 351(k)(4)(A)(i) of the PHS Act provides that one of the criteria for FDA to make a
determination of interchangeability is a finding that information in the application is sufficient to
show that the proposed interchangeable product is biosimilar to the reference product. Such
information would include, in part, a showing that the proposed interchangeable product meets
the highly similar standard for demonstrating biosimilarity.15 The “highly similar” standard
applies to both interchangeable and biosimilar products.
The product’s degree of structural and functional complexity may influence the extent of clinical
data needed to support a demonstration of interchangeability. For example, clinical data needed
to support a demonstration of interchangeability of a product expected to have a single target
(e.g., a receptor) may be more limited than the clinical data that may be needed for a product
acting on multiple targets or less-defined biological pathways. In addition, the extent of clinical
data needed may be affected by the presence of structural features that specifically impact
interchangeability (e.g., features that influence patient response to one product after exposure to
another product).
FDA acknowledges that there is a range of comparative analytical data that may be submitted to
support licensure under section 351(k) of the PHS Act.16 Data sets that include highly sensitive
analytics and/or sequential analytical methods that can identify molecules with different
combinations of attributes (e.g., charge variants and glycoforms), as well as a comprehensive
assessment of the relationships between attributes, may provide information that reduces the
14 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
15 Section 351(i)(2) of the PHS Act defines biosimilarity, in part, to mean “that the biological product is highly
similar to the reference product notwithstanding minor differences in clinically inactive components.”
16 See the guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
Product to a Reference Product (April 2015) for the Agency’s current thinking on factors to consider to support a
demonstration that a proposed therapeutic protein product is highly similar to a reference product.
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uncertainty about interchangeability. These approaches could be of greater importance for more
complex products because these products would have a larger number of attributes and thus a
potential for greater uncertainty regarding interchangeability. Advances in analytics may allow
for extended analytical characterization that affect the extent of other data and information
needed to support a demonstration of interchangeability and may in certain circumstances lead to
a more selective and targeted approach to clinical studies intended to support a demonstration of
interchangeability.
2. 	Product-Specific Immunogenicity Risk
Clinical experience with the reference product and comprehensive product risk assessments (e.g.,
regarding immunogenicity)17 may also affect the data and information needed to support a
demonstration of interchangeability. For example, products with a documented history of
inducing detrimental immune responses may require more data to support a demonstration of
interchangeability than products with an extensive documented history that immunogenicity does
not impact clinical outcomes.
3. 	Totality of Factors to Consider in Assessing the Data and Information Needed to
Support a Demonstration of Interchangeability
The factors discussed in sections V.A.1 and V.A.2 of this guidance need to be considered
together to inform the data and information needed to support a demonstration of
interchangeability in a particular context. Consider the following illustrative examples:
 	Product A and its associated reference product have relatively low structural complexity
and the reference product has no history of inducing severe immune responses related to
immunogenicity. Product A also has a low incidence of serious adverse events related to
immunogenicity, similar in nature and frequency to those observed with the reference
product, as demonstrated in clinical studies conducted as part of the development
program for Product A. Here, sufficiently extensive comparative analytical data
supporting a demonstration that the proposed interchangeable product (Product A) is
highly similar to the reference product, in addition to data derived from an appropriately
designed dedicated switching or integrated study (see section VI.A), may be sufficient to
support a demonstration of interchangeability.
 	Product B and its associated reference product have high structural complexity and the
reference product has a history of rare, life-threatening adverse events related to
immunogenicity. Here, postmarketing data for the product as a licensed biosimilar, in
addition to an appropriately designed switching study (see section VI.A), may provide
additional data and information necessary to support a demonstration of
interchangeability. The collection of biosimilar postmarketing data is described further in
section V.B of this guidance.
Based on the factors discussed in sections V.A.1 and V.A.2, the uncertainty regarding the
interchangeability of the respective proposed interchangeable products (described in the
17 Section VII.D.2 in the guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product (April 2015) provides a discussion on clinical immunogenicity assessment.
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preceding examples) would likely be different. Therefore, the data and information necessary to
support a demonstration of interchangeability need to be considered on a case-by-case basis.
B. 	Biosimilar Product Postmarketing Data That May Impact the Data Needed
to Support a Demonstration of Interchangeability
New tools and improved epidemiological approaches to evaluating postmarketing exposures and
outcomes lend promise to the continued improvement of the capabilities of postmarketing
surveillance and the collection of data related to the actual use of drug products in general.
However, our current thinking is that postmarketing data collected from products first licensed
and marketed as a biosimilar, without corresponding data derived from an appropriately
designed, prospective, controlled switching study or studies, generally would not be sufficient to
support a demonstration of interchangeability. For example, we generally would not expect
postmarketing data to provide sufficient information related to the impact on clinical
pharmacokinetics (PK) and pharmacodynamics (PD) of switching or alternating between the use
of the proposed interchangeable product and the reference product, which we think are important
study endpoint considerations in the switching studies for the reasons described in section VI.A.1
of this guidance.
Notwithstanding these limitations, we recognize that in certain circumstances, postmarketing
data from a licensed biosimilar product may be helpful as a factor when considering what data is
necessary to support a demonstration of interchangeability. For example, some sponsors may
wish to submit postmarketing data describing the real-world use of the biosimilar product,
including certain safety data related to patient experience with some switching scenarios. Such
data may reduce uncertainty about interchangeability and thus the data needed to support a
demonstration of interchangeability. FDA will evaluate proposals to include postmarketing data
in applications to support demonstrations of interchangeability on a case-by-case basis.
In certain situations, postmarketing surveillance data from the licensed biosimilar product in
addition to data from an appropriately designed switching study may be needed to address
uncertainty regarding a demonstration of interchangeability and add to the totality of the
evidence to support a demonstration of interchangeability. Further, there may be situations
where a postmarketing study, in addition to postmarketing surveillance data, from the licensed
biosimilar product may be needed to address uncertainty regarding a demonstration of
interchangeability. For example, as a scientific matter, for a reference product with a history of
severe immunogenicity-related adverse events, additional data and information may be needed to
support a demonstration of interchangeability. Such additional data may be able to be obtained
through collection of postmarketing information if the product has been licensed as a biosimilar.
Sponsors are encouraged to discuss with FDA their plans for the use of postmarketing data to
address any uncertainty about interchangeability and add to the totality of the evidence to support
a demonstration of interchangeability.
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VI. 	DATA AND INFORMATION NEEDED TO SUPPORT A DEMONSTRATION OF
INTERCHANGEABILITY
FDA recommends sponsors intending to develop a proposed interchangeable product to meet
with FDA to discuss their proposed product development plan. Early discussions with FDA
about product development plans, including adequate scientific justification for the proposed
development program, will facilitate development of interchangeable products.18
A. 	Considerations for the Design and Analysis of a Switching Study or Studies
Needed to Support a Demonstration of Interchangeability
A switching study or studies will generally be expected to demonstrate that “for a biological
product that is administered more than once to an individual, the risk in terms of safety or
diminished efficacy of alternating or switching between use of the biological product and the
reference product is not greater than the risk of using the reference product without such
alternation or switch” set forth in section 351(k)(4)(B) of the PHS Act. The main purpose of a
switching study or studies is to demonstrate that the risk in terms of safety or diminished efficacy
of alternating or switching between use of the proposed interchangeable product and the
reference product is not greater than the risk of using the reference product without such
alternation or switch. A switching study or studies should evaluate changes in treatment that
result in two or more alternating exposures (switch intervals) to the proposed interchangeable
product and to the reference product.
If a sponsor of a proposed interchangeable product believes that data from a switching study is
not necessary, FDA expects the sponsor to provide a justification for not needing such data as a
part of the demonstration of interchangeability. For biological products that are not intended to
be administered to an individual more than once, FDA expects that switching studies would
generally not be needed. For products intended to be administered more than once, sponsors are
encouraged to meet with FDA to discuss the planned development approach, including any
proposed justification of why data from a switching study is not needed.
Design of switching studies may be informed by how the proposed interchangeable product will
be used in clinical practice, taking into consideration scenarios where alternating or switching
products might cause the most clinical concern. For treatments that have a long course of
therapy, sponsors should anticipate dropouts in the study and should use a scientifically
justifiable method to address the increased possibility of missing data.
As described in more detail in this section, a switching study is typically designed to assess
whether switching between the reference product and the proposed interchangeable product will
present risk in terms of safety or diminished efficacy that is greater than using the reference
product without such switching. A switching study should generally evaluate whether switching
between the reference product and the proposed interchangeable product will affect clinical
18 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA
Products (June 2018), which provides recommendations to industry on all formal meetings between the FDA and
sponsors or applicants for proposed biosimilar products or proposed interchangeable products intended to be
submitted under 351(k) of the PHS Act. This draft guidance, when finalized, will represent FDA’s current thinking
on this topic.
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response in terms of safety or diminished efficacy reflected, in part, through an assessment of
whether switching results in differences in immunogenicity and PK and/or PD (if available), as
compared to not switching. If an apparent difference in clinical response in terms of safety or
diminished efficacy is noticed between the switching and non-switching arms of the study (see
section VI.A.2.a of this guidance), it would raise concerns as to whether the proposed
interchangeable product is interchangeable.
FDA has outlined a flexible approach regarding the design of a switching study. FDA will
address program-specific scientific matters (e.g., the impact of small patient populations) on a
case-by-case basis in interactions with sponsors. To facilitate development of interchangeable
products, FDA encourages sponsors to have early discussions with FDA about their product
development plans.
1. 	Study Endpoints
The primary endpoint in a switching study or studies should assess the impact of switching or
alternating between use of the proposed interchangeable product and the reference product on
clinical PK and PD (if available). The PK and PD (if available) endpoints, as distinguished from
clinical efficacy endpoints, are generally more likely to be sensitive to detect changes in
exposure and/or activity that may arise as a result of alternating or switching. In addition to PK
and/or PD parameters, a switching study would also be expected to descriptively assess
immunogenicity and safety. A switching study may also incorporate the evaluation of efficacy
endpoints. Although assessments of efficacy endpoints can be supportive, at therapeutic doses
many clinical efficacy endpoints would generally be less sensitive to detect changes in exposure
and/or activity that may arise as a result of alternating or switching.
Biologically relevant PD measures, if available, may be useful as shorter term, more sensitive
indicators of the potential impact of alternating or switching on the risk of diminished efficacy as
compared to efficacy endpoints. Relevant PD measures may also be useful to reflect multiple
domains of activity, which could reduce residual uncertainty about interchangeability. Selection
of PD endpoints should be scientifically justified for the intended purpose.19 When PD
endpoints that are sensitive to changes in drug concentration can be identified, PD analysis, in
addition to PK analysis, may be useful to assess the impact of switching or alternating between
the proposed interchangeable product and the reference product.
Study samples from the switching arm and non-switching arm should be assessed with the same
PK, PD, or immunogenicity assay. FDA recommends that clinical PK, PD, and immunogenicity
assays be developed and validated early in product development.20,21 Sponsors are expected to
demonstrate that the developed PK and/or PD assays are suitable for detecting changes on the
selected PK and/or PD endpoint(s) as a result of alternating or switching between products. The
19 See the guidance for industry, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a
Reference Product (December 2016).
20 See guidance for industry, Immunogenicity Testing of Therapeutic Protein Products—Developing and Validating
Assays for Anti-Drug Antibody Detection (January 2019).
21 See guidance for industry, Bioanalytical Method Validation (May 2018).
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validation study should demonstrate that the assay performs similarly for both the proposed
interchangeable product and the reference product.
In summary, the primary endpoint(s) in a switching study or studies are recommended to be, in
most cases, a comparison of PK and/or PD (if available) parameter(s) between the switching arm
and non-switching arm following the final switch. In cases where PK and/or PD are not
adequately sensitive endpoints (e.g., products with limited systemic exposure, or for which PD
effects are not measurable), sponsors are expected to propose and justify selected endpoints other
than PK or PD measures.
2. 	Study Design and Analysis
This section provides general recommendations and considerations related to study design and
analysis. Sponsors may propose alternative approaches and are encouraged to discuss the
proposed design and analysis of a switching study with FDA.
a. 	Dedicated Switching Study Design
A study with a lead-in period of treatment with the reference product, followed by a randomized
two-arm period—with one arm incorporating switching between the proposed interchangeable
product and the reference product (switching arm) and the other remaining as a non-switching
arm receiving only the reference product (non-switching arm)—may be appropriate when
designing a switching study. An illustrative example of switching study design is described in
Attachment I. Considerations for the design and analysis of such a study are discussed as
follows:
 	Sample size: The sample size of the switching study should generally be based on PK
considerations. Inter-subject variability in AUCtau or C max as described for the reference
product should be primary considerations; however, prior information on product
immunogenicity incidence and consequences should also be considered, and the sample
size should be appropriately justified. When appropriate, inter-subject variability in PD
endpoints may need to be considered. Study designers should anticipate the possibility of
a considerable dropout rate for reasons unrelated to the study treatment arms. An
anticipated high dropout rate due solely to an influence affecting all treatment arms could
be assumed to be random. The negative impact on the statistical power of such a random
influence could be precluded by factoring such influences into the sample size
calculation. It should be noted that dropout rates or missing data rates that differentially
affect the study treatment arms could represent treatment arm differences, and sponsors
should provide adequate justification to FDA about any such differences and their
possible causes. In addition, FDA will investigate possible causes of the noted
differences in treatment arms.
 	Number and duration of switches: The number and duration of switches between the
reference product and the proposed interchangeable product should take into
consideration the clinical condition to be treated, the therapeutic dosing of the product,
and the duration of the exposure period to each product that would be expected to cause
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the greatest concern in terms of immune response and resulting impact on safety and
efficacy, if any.
- 	The lead-in period should be of sufficient duration to ensure an adequate baseline
with respect to the study objectives before randomization to the switching period of
the study.
- 	The switching arm is generally expected to incorporate at least two separate exposure
periods (switch intervals) to each of the two products (i.e., at least three switches with
each switch crossing over to the alternate product).
- 	In the switching arm, the final switch should be from the reference product to the
proposed interchangeable product.
- 	The comparative assessment should occur during the final exposure period after a
sufficient time (i.e., an adequate washout period of at least three or more half-lives)
has elapsed following the last administration of the reference product in the switching
arm. The number of doses of the proposed interchangeable product or reference
product administered in the final exposure period will depend on the half-life and
clinical dosing regimen.
 	PK, PD, and immunogenicity sampling: To capture the full PK profile, intensive PK
sampling should be performed during the final exposure period after at least three half-
lives have elapsed following the last administration of the reference product in the
switching arm. Trough PK sampling should be conducted at an appropriate time point
during each exposure period to ensure that steady state is attained, when appropriate. The
timing of PD22 and immunogenicity23 sampling should be appropriately justified.
 	Study Analysis:
- 	Primary analysis: For intravenous (IV) studies, AUC tau will be considered a
primary study endpoint. For subcutaneous (SC) studies, Cmax and AUC tau will be
considered as co-primary study endpoints. The log-transformed AUCtau and C max
data should be statistically analyzed using an average equivalence statistical
approach.24 The 90% confidence interval for the geometric mean ratio of AUCtau
(IV and SC data) and Cmax (SC data) between the proposed interchangeable
product and the reference product should be within 80% to 125%. Ctrough and T max
22 See Section IV.H. Defining the Appropriate Pharmacodynamic Time Profile in the guidance for industry Clinical
Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (December 2016).
23 See Section VII.A. Obtaining Subject Samples in the guidance for industry Immunogenicity Testing of
Therapeutic Protein Products —Developing and Validating Assays for Anti-Drug Antibody Detection (January
2019). Also see Section IV. Recommendations for Mitigating Immunogenicity Risk in the Clinical Phase of
Development of Therapeutic Protein Products in the guidance for industry Immunogenicity Assessment of
Therapeutic Protein Product (August 2014).
24 See FDA’s guidance for industry Statistical Approaches to Establishing Bioequivalence (February 2001).
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should also be analyzed as secondary endpoints. The sponsor should propose
margins and statistical analyses appropriate for the evaluation of the PD
endpoints.
- 	Safety, immunogenicity, and efficacy should be descriptively assessed as
secondary endpoints. Regarding safety, it could be reasonable for a sponsor to
focus on an evaluation of all serious adverse events, immune-related safety
events, and adverse events of interest (e.g., known cardinal adverse events
previously described with use of the reference product). The immunogenicity
assessment should include, but not necessarily be limited to, an assessment of
anti-drug antibody (ADA) and neutralizing antibody (NAb) incidence, ADA and
NAb titer, and an evaluation of the impact of the development of ADA and NAb
on PK, PD, safety, and efficacy.25 Immunogenicity assays should be adequately
sensitive to detect ADA and NAb in the presence of drug concentrations in study
samples. Sponsors should discuss with FDA their planned evaluation of safety
and immunogenicity.
b. 	Integrated Study Design
If a sponsor is considering a single study to (1) support a demonstration of no clinically
meaningful differences between the reference product and the proposed product for
biosimilarity26 and (2) evaluate the impact of switching or alternating between the reference
product and the proposed product for interchangeability, then an integrated, two-part study
design may be appropriate. Following the time point(s) for evaluation of the appropriate
endpoint(s) to support the demonstration of no clinically meaningful differences for biosimilarity
between the proposed product and the reference product in the first part of the study, the subjects
in the reference product arm should be re-randomized in the second part of the study to continue
to receive the reference product (non-switching arm) or to switch to the proposed
interchangeable product (switching arm) as described in section VI.A.2.a of this guidance.
An integrated study needs to be adequately powered to evaluate the appropriate endpoint(s) to
support the demonstration of no clinically meaningful differences for biosimilarity, where the
primary comparison is between the proposed product arm and the reference product arm. In
addition, the study needs to be adequately powered to evaluate PK and PD (if available)
following the final switch to support a demonstration of interchangeability, where the primary
comparison is between the switching arm and the non-switching arm.
3. 	Study Population
The study population for switching studies should be adequately sensitive to allow for detection
of differences as a result of switching between the reference product and proposed
interchangeable product in PK and/or PD, common adverse events, and immunogenicity between
25 Refer to recommendations for immunogenicity assessments discussed in section VII of the guidance for industry
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).
26 Data and information needed to demonstrate biosimilarity are discussed in section VII of the guidance for industry
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).
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the switching and non-switching arms. FDA generally recommends that sponsors use patients in
switching studies because these studies are designed to assess the impact of switching and to
mimic how the proposed interchangeable product will be used in clinical practice. With
adequate scientific justification, however, sponsors may conduct switching studies in a patient
population that is different from that used to support licensure of the reference product, or in
healthy subjects. Sponsors should also provide adequate scientific justification to support that
the study population is adequately sensitive to detect the impact of switching (e.g., differences in
clinical PK and/or PD, common adverse events, and immunogenicity).
In a circumstance where a sponsor considers using healthy subjects, the sponsor should weigh
the benefit of exposing healthy subjects to a proposed interchangeable product and/or the
reference product during a clinical study against the risk of having them develop antibodies to
the product, which in turn may preclude them from being able to receive the treatment in the
future. However, there may be some limited situations where it is clinically and ethically
appropriate to use healthy subjects in switching studies. Sponsors are strongly encouraged to
discuss with FDA their rationale for conducting switching studies in healthy subjects before
initiating studies, preferably before submitting a proposed protocol or protocol amendment.
4. 	Condition(s) of Use to Be Studied
A sponsor may obtain licensure only for a condition(s) of use for which the reference product is
licensed. As described in section VI.B of this guidance, sponsors should consider choosing a
condition of use to study that would support subsequent extrapolation of data to other conditions
of use.
For example, if a reference product is licensed for multiple indications, one of which was
approved under section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR part
601, subpart E (accelerated approval), but the anticipated clinical benefit in that indication has
not yet been verified in postmarketing studies, then sponsors should consider studying another
indication for which the reference product is licensed, to avoid complications in the event that
postmarketing studies of the reference product fail to verify the anticipated clinical benefit in the
indication approved under accelerated approval.
5. 	Route of Administration
If a product is approved for more than one route of administration, sponsors should study the
route of administration that will best assess how a patient’s immune response will impact the
clinical performance of the proposed interchangeable product, including changes in safety risk
and efficacy. Choosing a more immunogenic route of administration (e.g., subcutaneous rather
than intravenous) for use in switching studies may help sponsors anticipate the clinical
implications of real-world use in clinical practice.
B. 	Extrapolation of Data
If the proposed product meets the statutory requirements for licensure as an interchangeable
product under section 351(k) of the PHS Act based on, among other things, data and information
sufficient to demonstrate interchangeability in an appropriate condition of use, the sponsor may
seek licensure of the proposed product as an interchangeable product for one or more additional
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conditions of use for which the reference product is licensed. The sponsor would need to
provide sufficient scientific justification for extrapolating data and information to support a
determination of interchangeability for each condition of use for which licensure as an
interchangeable product is sought. The scientific justification for extrapolation should address,
for example, the following issues for the tested and extrapolated conditions of use:
 	The mechanism(s) of action in each condition of use for which the reference product is
licensed, which may include the following:
- 	The target receptor(s) for each relevant activity/function of the product
- 	The binding, dose/concentration response, and pattern of molecular signaling upon
engagement of target receptor(s)
- 	The relationship between product structure and target/receptor interactions
- 	The location and expression of target receptor(s)
 	Differences, if any, in the expected PK and biodistribution of the product in different
patient populations (relevant PD measures may also provide important information on the
mechanism(s) of action)
 	Differences, if any, in the expected immunogenicity risk of the product in different
patient populations
 	Differences, if any, in expected toxicities in each condition of use and patient population
(including whether the expected toxicities are related to the pharmacological activity of
the product or to off-target activities)
 	Any other factor that may affect the safety or efficacy of the product in each condition of
use and patient population for which the reference product is licensed27
Differences between conditions of use with respect to the factors described above do not
necessarily preclude extrapolation. A scientific justification should address these differences in
the context of the totality of the evidence supporting a demonstration of interchangeability.
Advanced structural and functional characterization may provide additional support for the
justification for extrapolation.
In choosing a condition of use to study that would permit subsequent extrapolation of data to
other conditions of use, FDA recommends that a sponsor consider a condition of use that would
be adequately sensitive to assess the risk of alternating or switching between the products, in
terms of safety or diminished efficacy, in a switching study.
27 These factors are also discussed in section VII.D.4. Extrapolation of Clinical Data Across Indications in the
guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).
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VII. 	CONSIDERATIONS REGARDING THE COMPARATOR PRODUCT IN A
SWITCHING STUDY OR STUDIES
As defined in section 351(i)(3) of the PHS Act, an interchangeable product may be substituted
for the reference product without the prescribing health care provider’s intervention. As
described above, sponsors will generally be expected to conduct a switching study or studies to
address section 351(k)(4)(B) of the PHS Act: “for a biological product that is administered more
than once to an individual, the risk in terms of safety or diminished efficacy of alternating or
switching between use of the biological product and the reference product is not greater than the
risk of using the reference product without such alternation or switch.” The goal of a switching
study or studies is to support a determination that a biosimilar product is interchangeable with a
reference product that is licensed for use in the United States.
If a sponsor seeks to use data derived from a switching study or studies comparing a proposed
interchangeable product with a non-U.S.-licensed comparator product as part of the
demonstration that the proposed interchangeable product meets the standard described in section
351(k)(4)(B) of the PHS Act, the sponsor should provide adequate data and information to
establish a “bridge” between the non-U.S.-licensed comparator and the U.S.-licensed reference
product and thereby justify the relevance of the data obtained using the non-U.S.-licensed
comparator to an evaluation of whether the requirements of section 351(k)(4)(B) have been met.
This section describes considerations for the type and extent of data needed to establish an
adequate bridge in this context.
In the context of demonstrating biosimilarity to a reference product, FDA has stated that
“sponsors may seek to use data derived from animal or clinical studies comparing a proposed
product with a non-U.S.-licensed comparator product to address, in part, the requirements under
section 351(k)(2)(A) of the PHS Act.”28,29 In clinical studies used to support a demonstration of
no clinically meaningful differences as a part of demonstrating biosimilarity, the comparator
product (whether it is a non-U.S.-licensed product or a U.S.-licensed reference product) serves as
a control against which the proposed product is evaluated. However, in a switching study that is
designed to evaluate the impact of switching or alternating to support a determination of
interchangeability, the comparator product plays a different role.
As described in section VI.A., a switching study is typically designed to assess whether
switching between the reference product and the proposed interchangeable product will present
risk in terms of safety or diminished efficacy that is greater than using the reference product
without such switching. A switching study should generally evaluate whether switching between
the reference product and the proposed interchangeable product will affect clinical response in
terms of safety or diminished efficacy reflected, in part, through an assessment of whether
switching results in differences in immunogenicity and PK and/or PD (if available), as compared
28 See section V on U.S.-licensed reference product and other comparators in the guidance for industry Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).
29 See Q.I.8 in the guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act
(December 2018), which discusses use of a non-U.S.-licensed product to support a demonstration that the proposed
product is biosimilar to the reference product.
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to not switching. Hence, rather than being used only as a control, the comparator product is used
in a switching study in both the active switching arm and the control non-switching arm.
Therefore, the type and extent of bridging data needed to justify the use of a non-U.S.-licensed
comparator in a switching study may be different or more extensive than is needed in other
contexts.
It is possible that the reference product and the non-U.S.-licensed comparator product have, for
example, subtle differences in levels of specific structural features (e.g., acidic variants,
deamidations), process related impurities, or formulation. These subtle differences may not
preclude use of the non-U.S.-licensed product as a comparator in certain studies to support a
demonstration of biosimilarity because the comparator is being used as a control in an evaluation
that does not involve switching back and forth. However, in the context of switching between
the products, multiple exposures to each product may potentially prime the immune system to
recognize subtle differences in structural features between products. The overall immune
response could be increased under these conditions. This immunologic response is highly
dependent on the structural differences between the proposed interchangeable product and the
comparator product used in the switching study, in addition to other potential differences
between the products such as impurities and formulation.
For the reasons described above, the type and extent of data needed to justify the use of a non-
U.S.-licensed comparator in a switching study may be different or more extensive than is needed
in other contexts in which a non-U.S.-licensed comparator is used. However, FDA believes that
when supported by adequate data and information, it may be reasonable to use a non-U.S.-
licensed comparator in a switching study. Sponsors are encouraged to contact FDA early in the
product development process to discuss the design of a switching study, including any proposal
to provide adequate scientific justification to support the use of data generated in a switching
study using a non-U.S.-licensed comparator product to support a demonstration of
interchangeability.
VIII. 	CONSIDERATIONS FOR DEVELOPING PRESENTATIONS FOR PROPOSED
INTERCHANGEABLE PRODUCTS
The data and information needed to support a demonstration of interchangeability, beyond that
needed to demonstrate biosimilarity,30 may also be influenced by the proposed product’s
presentation.31 Sponsors are encouraged to contact FDA early during product development to
discuss the proposed presentation and specific considerations related to licensure of the proposed
product as an interchangeable under section 351(k) of the PHS Act.
30 Data and information needed to demonstrate biosimilarity are discussed in section VII of the guidance for industry
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).
31 For the purposes of this guidance, the term presentation means the container closure system and any delivery
device constituent part of the product.
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When developing a product for licensure as an interchangeable product under section 351(k) of
the PHS Act, it is important that sponsors carefully consider the presentation of the proposed
interchangeable product relative to the reference product.32 A sponsor developing an
interchangeable product generally should not seek licensure for a presentation for which the
reference product is not licensed. For example, if the reference product is only marketed in a
vial and a prefilled syringe, a sponsor should not seek licensure for the proposed interchangeable
product for a different presentation, such as an auto-injector. However, if a sponsor is
considering the development of a presentation for which the reference product is not licensed,
this should be discussed with FDA. In such cases, FDA will evaluate whether the proposed
presentation could support a demonstration of interchangeability.
As applicable, a general description of the presentation should be provided in the chemistry,
manufacturing, and controls section of the application. There should be complete chemistry,
manufacturing, and controls information for the proposed interchangeable product, including, if
applicable, delivery device constituent part design, and development information. The
presentation should be shown to be compatible for use with the final formulation of the proposed
interchangeable product through appropriate studies, including, for example,
extractable/leachable studies, performance testing, and stability studies. Data and information
supporting the appropriate use and performance testing of the delivery device constituent part of
the proposed interchangeable product should be submitted.
IX. 	POSTMARKETING SAFETY MONITORING CONSIDERATIONS
Robust postmarketing safety monitoring is an important component in ensuring the safety and
effectiveness of biological products, including biosimilar and interchangeable products.
Postmarketing safety monitoring for interchangeable products should first take into consideration
any particular safety or effectiveness concerns associated with the use of the reference product
and its class, the proposed interchangeable product in its development and clinical use (if
marketed outside the United States), the specific condition of use and patient population, and
patient exposure in the interchangeability development program. Postmarketing safety
monitoring for an interchangeable product should also have adequate pharmacovigilance
mechanisms in place.33 Rare but potentially serious safety risks may not be detected during
preapproval clinical testing because the size of the population exposed likely will not be large
enough to assess rare events. In particular cases, such risks may need to be evaluated through
32 See Q.I.4 and Q.I.6 in the guidance for industry Questions and Answers on Biosimilar Development and the BPCI
Act (December 2018).
33 For general pharmacovigilance considerations, see the guidance for industry Good Pharmacovigilance Practices
and Pharmacoepidemiologic Assessment (March 2005) and the guidance for industry Postmarketing Adverse
Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report (August
1997).
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postmarketing surveillance or studies. In addition, as with any other biological product, FDA
may require a postmarketing study or a clinical trial to evaluate certain safety risks.34
Because some aspects of postmarketing safety monitoring are product-specific and dependent
upon the risk that is the focus of monitoring, FDA encourages sponsors to consult with
appropriate FDA divisions to discuss the sponsor’s proposed approach to postmarketing safety
monitoring.
34 See section 505(o)(3) and 505(p)(1)(A)(ii) of the Federal Food, Drug, and Cosmetic Act.
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ATTACHMENT I
Example of a Switching Study Design
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