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 

 
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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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  Contains Nonbinding Recommendations 
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, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 patient5 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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  Contains Nonbinding Recommendations 
 	  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 sponsors 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 products 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.)   
 
3 

  Contains Nonbinding Recommendations 
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 products identity, quantity, safety, purity and  
potency.  See the ICH guidance for industry  Q8(R2) Pharmaceutical Development (November 2009). 
 
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  Contains Nonbinding Recommendations 
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 products 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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  Contains Nonbinding Recommendations 
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 products 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 Agencys current thinking on factors  to consider  to  support a  
demonstration that a proposed  therapeutic protein product is  highly similar to a  reference  product.  
 
6 

  Contains Nonbinding Recommendations 
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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  Contains Nonbinding Recommendations 
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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  Contains Nonbinding Recommendations 
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 FDAs current thinking  
on this topic.  
9 

  Contains Nonbinding Recommendations 
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 ProductsDeveloping and Validating 
Assays for Anti-Drug Antibody Detection (January  2019).  
 
21 See guidance  for  industry,  Bioanalytical Method Validation  (May 2018).   
10 

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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 periodwith 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 AUC  or C  as described for the reference 
tau max
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 
11 

  Contains Nonbinding Recommendations 
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, AUCtau will be considered a 
primary study endpoint.  For subcutaneous (SC) studies, C  and AUC  will be 
max tau
considered as co-primary study endpoints.  The log-transformed AUC  and C  
tau max 
data should be statistically analyzed using an average equivalence statistical 
approach.24  The 90% confidence interval for the geometric mean ratio of AUC  
tau 
(IV and SC data) and C  (SC data) between the proposed interchangeable 
max
product and the reference product should be within 80% to 125%. C  and T  
trough 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 FDAs guidance for  industry Statistical Approaches to Establishing  Bioequivalence (February 2001).   
12 

  Contains Nonbinding Recommendations 
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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  Contains Nonbinding Recommendations 
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 patients 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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  Contains Nonbinding Recommendations 
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 providers 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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  Contains Nonbinding Recommendations 
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 products 
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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  Contains Nonbinding Recommendations 
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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  Contains Nonbinding Recommendations 
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 sponsors 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. 
 
19 

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ATTACHMENT I 
 
 
Example of a Switching Study Design 
	
 
 
 
20