Questions and 
Answers on Biosimilar 
Development and the 
BPCI Act 
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) 
 
September 2021 
Biosimilars 
 
Revision 2 
 
    
Questions and Answers on 
Biosimilar Development 
and the BPCI Act  
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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 Food and Drug Administration 
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Email:  ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances  
 
 
 
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) 
 
September 2021 
Biosimilars 
 
Revision 2 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
INTRODUCTION......................................................................................................................... 1 
BACKGROUND ........................................................................................................................... 2 
QUESTIONS AND ANSWERS ................................................................................................... 4 
I.  BIOSIMILARITY OR INTERCHANGEABILITY ........................................................................... 4 
Q.I.1.  Whom should a sponsor contact with questions about its proposed development program for 
a proposed biosimilar product or a proposed interchangeable product? ............................................ 4 
Q.I.2.  When should a sponsor request a meeting with FDA to discuss its development program for 
a proposed biosimilar product or a proposed interchangeable product, and what data and 
information should a sponsor provide to FDA as background for this meeting? ................................ 4 
Q.I.3.  Can a proposed biosimilar product have a formulation that is different from the reference 
product? ............................................................................................................................................... 5 
Q.I.4.  Can a proposed biosimilar product have a delivery device or container closure system that 
is different from its reference product? ................................................................................................ 5 
Q.I.5.  Can an applicant obtain licensure of a proposed biosimilar product for fewer than all 
routes of administration for which an injectable reference product is licensed? ................................ 6 
Q.I.6.  Can an applicant obtain licensure of a proposed biosimilar product for fewer than all 
presentations (e.g., strengths or delivery device or container closure systems) for which a reference 
product is licensed? .............................................................................................................................. 6 
Q.I.7.  Can an applicant obtain licensure of a proposed biosimilar product for fewer than all 
conditions of use for which the reference product is licensed? ............................................................ 7 
Q.I.8.  Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to 
support a demonstration that the proposed product is biosimilar to the reference product? .............. 7 
Q.I.9.  Is a clinical study to assess the potential of the biological product to delay cardiac 
repolarization (a QT/QTc study) or a drug-drug interaction study generally needed for licensure of 
a proposed biosimilar product? ........................................................................................................... 9 
Q.I.10.  How long and in what manner should sponsors retain reserve samples of the biological 
products used in comparative clinical PK and/or PD studies intended to support a 351(k) 
application? ........................................................................................................................................ 10 
Q.I.13.  What constitutes publicly-available information regarding FDAs previous 
determination that the reference product is safe, pure, and potent to include in a 351(k) application?  
     ............................................................................................................................................. 11 
Q.I.14.  Can an applicant obtain a determination of interchangeability between its proposed 
product and the reference product in an original 351(k) application? .............................................. 11 
Q.I.15.  Is a pediatric assessment under the Pediatric Research Equity Act (PREA) required for a 
proposed biosimilar product? ............................................................................................................ 12 
Q.I.16.  How can a proposed biosimilar product applicant fulfill the requirement for pediatric 
assessments or investigations under PREA? ...................................................................................... 13 
i  Contains Nonbinding Recommendations 
 
Q.I.17.  When should a proposed biosimilar product applicant submit an initial pediatric study 
plan (PSP)? ........................................................................................................................................ 16 
Q.I.18.  For biological products intended to be injected, how can an applicant demonstrate that its 
proposed biosimilar product has the same dosage form as the reference product? .......................... 17 
Q.I.19.  If a non-U.S.-licensed product is proposed for importation and use in the United States in 
a clinical investigation intended to support licensure of a proposed product under section 351(k) 
(e.g., a bridging clinical PK and/or PD study), is a separate IND required for the non-U.S.-licensed 
product?  ............................................................................................................................................. 17 
Q.I.20.  What is the nature and type of information that a sponsor should provide to support a 
postapproval manufacturing change for a licensed biosimilar product? .......................................... 19 
Q.I.21.  May a sponsor seek approval, in a 351(k) application or a supplement to an approved 
351(k) BLA, of a route of administration, a dosage form, or a strength that is different from that of 
the reference product?........................................................................................................................ 20 
Q.I.22.  May a sponsor seek approval, in a 351(k) application or a supplement to an approved 
351(k) BLA, for a condition of use that has not previously been approved for the reference product?  
     ............................................................................................................................................. 21 
Q.I.24.  May an applicant submit data and information to support approval of a proposed 
biosimilar or interchangeable product for an indication for which the reference product has 
unexpired orphan exclusivity? ............................................................................................................ 21 
II.  PROVISIONS RELATED TO REQUIREMENT TO SUBMIT A BLA FOR A BIOLOGICAL 
PRODUCT .......................................................................................................................................... 22 
Q.II.2.  How is product class defined for purposes of determining whether an application for a 
biological product may be submitted under section 505 of the FD&C Act during the transition 
period?   ............................................................................................................................................. 22 
Q.II.3.  What type of marketing application should be submitted for a proposed antibody-drug 
conjugate? .......................................................................................................................................... 23 
III. EXCLUSIVITY .................................................................................................................................... 24 
Q.III.1.  Can an applicant include in its 351(a) BLA submission a request for reference product 
exclusivity under section 351(k)(7) of the PHS Act? .......................................................................... 24 
Q.III.2.  How can a prospective biosimilar applicant determine whether there is unexpired orphan 
exclusivity for an indication for which the reference product is licensed? ........................................ 24 
ii  Contains Nonbinding Recommendations 
Questions and Answers on Biosimilar Development  
and the BPCI Act 
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.   
 
 
 
 
INTRODUCTION  
 
This guidance document provides answers to common questions from prospective applicants and 
other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 
(BPCI Act).  The question and answer (Q&A) format is intended to inform prospective 
applicants and facilitate the development of proposed biosimilars and interchangeable 
biosimilars,2 as well as describe FDAs interpretation of certain statutory requirements added by 
the BPCI Act. 
 
The BPCI Act created an abbreviated licensure pathway in section 351(k) of the Public Health 
Service Act (PHS Act) for biological products shown to be biosimilar to, or interchangeable 
with, an FDA-licensed biological reference product (see sections 7001 through 7003 of the 
Patient Protection and Affordable Care Act (Pub. L. 111148) (ACA)).  FDA believes that 
guidance for industry that provides answers to commonly asked questions regarding FDAs 
interpretation of the BPCI Act will enhance transparency and facilitate the development and 
approval of biosimilar and interchangeable products.  In addition, these Q&As respond to 
questions the Agency has received from applicants regarding the submission of biologics license 
applications (BLAs) for biosimilar and interchangeable products.  FDA intends to update this 
final guidance document to include additional Q&As as appropriate. 
 
1 This guidance was prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics 
Evaluation and Research (CBER) at the Food and Drug Administration (FDA or the Agency).  We update guidances 
periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page 
at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
2 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 also determined to be interchangeable with the 
reference product (see sections 351(i)(3) and 351(k)(4) of the PHS Act).  The terms proposed biosimilar product 
and proposed interchangeable product are used to describe a product that is under development or is the subject of a 
pending 351(k) BLA.  Biosimilarity, interchangeability, and related issues are discussed in more detail in the 
BACKGROUND section of this guidance. 
  1  Contains Nonbinding Recommendations 
 
This final guidance document is part of a series of guidance documents that FDA developed to 
facilitate development of biosimilar and interchangeable products. 
 
The final guidance documents issued to date address a broad range of issues, including: 
  Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference 
Product (December 2016) 
  Considerations in Demonstrating Interchangeability With a Reference Product (May 
2019) 
  Labeling for Biosimilar Products (July 2018) 
  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 
2015) 
 
In addition, FDA has published draft guidance documents related to the BPCI Act, which, when 
finalized, will represent FDAs current thinking.  These draft guidance documents include: 
  Biosimilarity and Interchangeability:  Additional Draft Q&As on Biosimilar 
Development and the BPCI Act (November 2020) 
  Development of Therapeutic Protein Biosimilars:  Comparative Analytical Assessment 
and Other Quality-Related Considerations (May 2019) 
  Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products 
(June 2018) 
  New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) 
(September 2021) 
  Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the 
PHS Act (August 2014) 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law.  
FDA guidance documents, including this guidance, 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.  
 
 
BACKGROUND 
 
The BPCI Act 
 
The BPCI Act was enacted as part of the ACA on March 23, 2010.  The BPCI Act amended the 
PHS Act and other statutes to create an abbreviated licensure pathway for biological products 
shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product 
  2  Contains Nonbinding Recommendations 
(see sections 7001 through 7003 of the ACA).  Section 351(k) of the PHS Act (42 U.S.C. 
262(k)), added by the BPCI Act, sets forth the requirements for the licensure of a proposed 
biosimilar or proposed interchangeable biosimilar. 
 
Section 351(i) defines biosimilarity to mean that the biological product is highly similar to the 
reference product notwithstanding minor differences in clinically inactive components 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 (see section 351(i)(2) of the 
PHS Act). 
 
A BLA submitted under section 351(k) (a 351(k) BLA) must contain, among other things, 
information demonstrating that the biological product is biosimilar to a reference product based 
upon data derived from analytical studies, animal studies, and a clinical study or studies (see 
section 351(k)(2)(A)(i)(I) of the PHS Act).  FDA has the discretion to determine that an element 
described in section 351(k)(2)(A)(i)(I) is unnecessary in a 351(k) BLA (see section 
351(k)(2)(A)(ii) of the PHS Act).  To meet the standard for interchangeability, an applicant 
must provide sufficient information to demonstrate biosimilarity to the reference product and 
also to demonstrate that the biological product can be expected to produce the same clinical 
result as the reference product in any given patient, and if the biological product is administered 
more than once to an individual, the risk in terms of safety or diminished efficacy of alternating 
or switching between the 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 (see section 
351(k)(4) of the PHS Act).  Interchangeable products may be substituted for the reference 
product without the intervention of the prescribing healthcare provider (see section 351(i)(3) of 
the PHS Act). 
 
Biosimilar Development and the BPCI Act Question and Answer Guidance Format 
 
The Q&A guidances for biosimilars contain Q&As about biosimilar and interchangeable 
products.  This guidance includes all Q&As that are in final form.  The draft guidance 
Biosimilarity and Interchangeability:  Additional Draft Q&As on Biosimilar Development and 
the BPCI Act (Additional Draft Q&A Guidance) (November 2020) and the draft guidance New 
and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) (New and 
Revised Draft Q&A Guidance) (September 2021) contain Q&As that are draft.  After FDA has 
considered any comments on the Q&As contained in the draft guidances received during the 
relevant comment period and, as appropriate, incorporated suggested changes to the Q&A, 
individual Q&As will be moved to the final guidance document.  FDA will endeavor to maintain 
one Q&A guidance in draft and the other Q&A guidance in final.   
 
FDA will provide the publication date of the current version of each Q&A, and information 
about whether the Q&A has been added to or modified in this final guidance document.  FDA 
has maintained the original numbering of the guidance Q&As used in the December 2018 final 
guidance document (Questions and Answers on Biosimilar Development and the BPCI Act) and 
December 2018 draft guidance document (New and Revised Draft Q&As on Biosimilar 
Development and the BPCI Act (Revision 2)), and the Additional Draft Q&A Guidance.  For ease 
of reference, a Q&A retains the same number when it moves from a draft guidance document to 
  3  Contains Nonbinding Recommendations 
the final guidance document and, where appropriate, when a Q&A is withdrawn from the final 
guidance document and moved to a draft guidance document.  When Q&As from the Additional 
Draft Q&A Guidance and New and Revised Draft Q&A Guidance are finalized and moved to the 
final guidance document, the final guidance document will clearly identify the draft guidance in 
which the Q&As were issued. 
 
A Q&A that was previously in the final guidance document may be withdrawn and moved to a 
draft guidance document if FDA determines that the Q&A should be revised and reissued in a 
revised draft Q&A for comment.  A Q&A also may be withdrawn and removed from the Q&A 
guidance documents if, for instance, the issue addressed in the Q&A is addressed in another 
FDA guidance document. 
 
Where a Q&A has been withdrawn from a draft or final guidance document, this is marked in the 
final guidance document by several asterisks between nonconsecutively numbered Q&As, and 
where appropriate, explanatory text.   
 
 
QUESTIONS AND ANSWERS 
 
I.  BIOSIMILARITY OR INTERCHANGEABILITY 
 
Q.I.1.  Whom should a sponsor contact with questions about its proposed development 
program for a proposed biosimilar product or a proposed interchangeable 
product? 
[Final December 2018] 
 
A.I.1.  FDA provides current contact information on its website, Biosimilars, available 
at https://www.fda.gov/biosimilars (click on the link, Industry Information and 
Guidance listed in the left column). 
 
Q.I.2.  When should a sponsor request a meeting with FDA to discuss its development 
program for a proposed biosimilar product or a proposed interchangeable 
product, and what data and information should a sponsor provide to FDA as 
background for this meeting? 
[Final December 2018] 
 
A.I.2.  See FDAs draft guidance for industry Formal Meetings Between the FDA and 
Sponsors or Applicants of BsUFA Products,3 for a description of the different 
meeting types intended to facilitate biosimilar development programs in 
accordance with the Biosimilar User Fee Act of 2012 (BsUFA), as reauthorized 
by the Biosimilar User Fee Amendments of 2017 (BsUFA II) and the criteria/data 
needed to support the request.  The type of meeting granted will depend on the 
 
3 This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
  4  Contains Nonbinding Recommendations 
stage of product development and whether the information submitted in the 
meeting package meets the criteria for the type of meeting.  
 
Q.I.3.  Can a proposed biosimilar product have a formulation that is different from the 
reference product? 
[Updated/Retained in Final September 2021] 
 
A.I.3.  Differences between the formulation of a proposed biosimilar product and the 
reference product may be acceptable.  A 351(k) application must contain 
information demonstrating that the biological product is highly similar to the 
reference product notwithstanding minor differences in clinically inactive 
components.  In addition, an applicant would need to demonstrate that there are 
no clinically meaningful differences between the biological product and the 
reference product in terms of safety, purity, and potency.  It may be possible, for 
example, for a proposed biosimilar product formulated without human serum 
albumin to demonstrate biosimilarity to a reference product formulated with 
human serum albumin.  For more information about FDAs current thinking on 
the interpretation of the statutory standard for biosimilarity, see FDAs guidance 
for industry Scientific Considerations in Demonstrating Biosimilarity to a 
Reference Product, and draft guidance for industry Development of Therapeutic 
Protein Biosimilars:  Comparative Analytical Assessment and Other Quality-
Related Considerations.4  
 
Q.I.4.  Can a proposed biosimilar product have a delivery device or container closure 
system that is different from its reference product? 
[Updated/Retained in Final September 2021] 
 
A.I.4.  Some design differences in the delivery device or container closure system used 
with the proposed biosimilar product may be acceptable, as long as the proposed 
product meets the standards for biosimilarity, including that such differences 
would not result in a condition of use that has not been previously approved for 
the reference product or a dosage form, strength, or route of administration that 
differs from that of the reference product.  It may be possible, for example, for an 
applicant to obtain licensure of a proposed biosimilar product in a prefilled 
syringe or in an auto-injector device (which are considered the same dosage 
form), even if the reference product is licensed in a vial presentation, provided 
that the proposed biosimilar product meets the statutory standard for biosimilarity  
and adequate performance data for the delivery device or container closure system 
are provided.  For a proposed biosimilar product in a different delivery device or 
container closure system, as a scientific matter, the delivery device or container 
closure system must be shown to be compatible for use with the final formulation 
of the biological product through appropriate studies, including, for example, 
extractable/leachable studies and stability studies.  Also, for design differences in 
 
4 This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
  5  Contains Nonbinding Recommendations 
the delivery device or container closure system, performance testing and a human 
factors study may be needed. 
 
However, an applicant will not be able to obtain licensure of a proposed 
biosimilar product when a design difference in the delivery device or container 
closure system results in any of the following:  
  A clinically meaningful difference between the proposed biosimilar product 
and the reference product in terms of safety, purity, and potency; 
  A different route of administration; 
  A condition of use (e.g., indication, dosing regimen) for which the reference 
product has not been previously approved; or 
  A proposed biosimilar product that otherwise does not meet the standard for 
biosimilarity. 
 
A proposed biosimilar product in a delivery device will be considered a 
combination product and may, in some instances, require a separate application 
for the device.  
 
Q.I.5.  Can an applicant obtain licensure of a proposed biosimilar product for fewer 
than all routes of administration for which an injectable reference product is 
licensed? 
[Final April 2015] 
 
A.I.5.  Yes.  An applicant may obtain licensure of a proposed biosimilar product for 
fewer than all routes of administration for which an injectable reference product is 
licensed.  An applicant must demonstrate that there are no clinically meaningful 
differences between the proposed biosimilar product and the reference product in 
terms of safety, purity, and potency.  In a limited number of circumstances, this 
may include providing information from one or more studies using a route of 
administration for which licensure is not requested (e.g., a study using 
subcutaneous administration may provide a more sensitive comparative 
assessment of immunogenicity of the reference product and a proposed biosimilar 
product, even though licensure of the proposed biosimilar product is requested 
only for the intravenous route of administration). 
 
Q.I.6.  Can an applicant obtain licensure of a proposed biosimilar product for fewer 
than all presentations (e.g., strengths or delivery device or container closure 
systems) for which a reference product is licensed?  
[Final December 2018] 
 
A.I.6.  An applicant is not required to obtain licensure of a proposed biosimilar product 
for all presentations for which the reference product is licensed.  However, if an 
applicant seeks licensure for a particular indication or other condition of use for 
which the reference product is licensed and that indication or condition of use 
  6  Contains Nonbinding Recommendations 
corresponds to a certain presentation of the reference product, the applicant may 
need to seek licensure for that particular presentation (see also Q&As I.4 and I.5). 
 
Q.I.7.  Can an applicant obtain licensure of a proposed biosimilar product for fewer 
than all conditions of use for which the reference product is licensed?  
[Final December 2018] 
 
A.I.7.  An applicant generally may obtain licensure of a proposed biosimilar product for 
fewer than all conditions of use for which the reference product is licensed.  The 
351(k) application must include information demonstrating that the condition or 
conditions of use prescribed, recommended, or suggested in the proposed labeling 
submitted for the proposed biosimilar product have been previously approved for 
the reference product (see section 351(k)(2)(A)(i)(III) of the PHS Act).   
 
For information about the licensure of a proposed interchangeable product, see 
FDAs guidance for industry Considerations in Demonstrating Interchangeability 
With a Reference Product.5 
 
Q.I.8.  Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed 
product to support a demonstration that the proposed product is biosimilar to 
the reference product?  
[Updated/Retained in Final September 2021] 
 
A.I.8.  A sponsor may use a non-U.S.-licensed comparator product in certain studies to 
support a demonstration that the proposed biological product is biosimilar to the 
U.S.-licensed reference product.  However, as a scientific matter, analytical 
studies and at least one clinical pharmacokinetic (PK) study, which may include 
pharmacodynamic (PD) endpoint(s) intended to support a demonstration of 
biosimilarity, must include an adequate comparison of the proposed biosimilar 
product directly with the U.S.-licensed reference product unless it can be 
scientifically justified that such a study is not needed.   
 
If a sponsor seeks to use data from an animal study6 or a clinical study comparing 
its proposed biosimilar product to a non-U.S.-licensed product to address, in part, 
the requirements under section 351(k)(2)(A) of the PHS Act, the sponsor should 
provide adequate data or information to scientifically justify the relevance of 
these comparative data to an assessment of biosimilarity and establish an 
acceptable bridge to the U.S.-licensed reference product.  As a scientific matter, 
the type of bridging data needed will always include data from analytical studies 
 
5 As explained in that guidance, FDA generally expects that applicants seeking to demonstrate interchangeability 
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. 
6 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider if such an alternative method could be assessed for equivalency 
to an animal test method. 
  7  Contains Nonbinding Recommendations 
(e.g., structural and functional data) that directly compare all three products (i.e., 
the proposed biosimilar product, the U.S.-licensed reference product, and the non-
U.S.-licensed comparator product), and is likely to also include bridging clinical 
PK data or, when appropriate, PD data, for all three products.  All three pairwise 
comparisons should meet the prespecified acceptance criteria for analytical and 
PK or PD similarity.  The acceptability of such an approach will be evaluated on a 
case-by-case basis, and should be discussed in advance with the Agency.  For 
certain complex biological products, a modified approach may be needed.  A final 
determination about the adequacy of the scientific justification and bridge will be 
made during the review of the application.   
 
Issues that a sponsor may need to address to use a non-U.S.-licensed comparator 
product in a biosimilar development program include but are not limited to the 
following: 
  Relevance of the design of the clinical program to support a demonstration of 
biosimilarity to the U.S.-licensed reference product for the condition(s) of use 
and patient population(s) for which licensure is sought 
  Relationship between the license holder for the non-U.S.-licensed comparator 
product and BLA holder for the U.S.-licensed reference product 
  Whether the non-U.S.-licensed comparator product was manufactured in a 
facility(ies) licensed and inspected by a regulatory authority that has similar 
scientific and regulatory standards as FDA (e.g., International Conference on 
Harmonisation (ICH) countries) 
  Whether the non-U.S.-licensed comparator product was licensed by a 
regulatory authority that has similar scientific and regulatory standards as 
FDA (e.g., ICH countries) and the duration and extent to which the product 
has been marketed 
  Scientific bridge between the non-U.S.-licensed comparator product and the 
U.S.-licensed reference product, including comparative physicochemical 
characterization, biological assays/functional assays, degradation profiles 
under stressed conditions, and comparative clinical PK or, when appropriate, 
PD data, to address the impact of any differences in formulation or primary 
packaging on product performance 
 
A sponsor should also address any other factors that may affect the relevance of 
comparative data with the non-U.S.-licensed comparator product to an assessment 
of biosimilarity with the U.S.-licensed reference product. 
 
A sponsor may submit publicly available information regarding the non-U.S.-
licensed comparator product to justify the extent of comparative data needed to 
establish a bridge to the U.S.-licensed reference product.  The complexity of the 
products, particularly with respect to higher order structure, post-translational 
modifications (e.g., glycosylation), and the degree of heterogeneity associated 
with the product may affect the considerations for the scientific justification 
  8  Contains Nonbinding Recommendations 
regarding the extent of bridging data.  Additional factors that FDA may consider 
regarding the extent of bridging data include but are not limited to the following: 
  Whether the formulation, dosage form, and strength of the U.S.-licensed 
reference product and non-U.S.-licensed comparator products are the same 
  Route of administration of the U.S.-licensed reference product and non-U.S.-
licensed comparator products 
  Design of the physicochemical and biological/functional assessments and the 
use of multiple orthogonal methods with adequate sensitivity to detect 
differences among the products 
  Scientific justification for the selection of the non-U.S.-licensed comparator 
lots used to establish the scientific bridge and how the selected lots relate to 
the material used in the nonclinical and clinical studies; the scientific bridge 
should include a sufficient number of lots of non-U.S.-licensed comparator 
product to adequately capture the variability in product quality attributes, and 
when possible, the non-U.S.-licensed comparator lots used in the nonclinical 
or clinical studies should be included in the assessment performed to establish 
the analytical bridge 
 
Sponsors are encouraged to discuss with FDA during the development program 
the adequacy of the scientific justification and bridge to the U.S.-licensed 
reference product.  A final decision about the adequacy of this scientific 
justification and bridge will be made by FDA during review of the 351(k) 
application. 
 
For more information about whether a non-U.S.-licensed comparator can be used 
in studies intended to support the additional criteria required for a determination 
of interchangeability with the reference product, see FDAs guidance for industry 
Considerations in Demonstrating Interchangeability With a Reference Product. 
 
Q.I.9.  Is a clinical study to assess the potential of the biological product to delay 
cardiac repolarization (a QT/QTc study) or a drug-drug interaction study 
generally needed for licensure of a proposed biosimilar product? 
[Final December 2018] 
 
A.I.9.  In general, a 351(k) application for a proposed biosimilar product may rely upon 
the Agencys previous determination of safety, purity, and potency for the 
reference product, including any clinical QT/QTc interval prolongation and 
proarrhythmic potential and drug-drug interactions.  If such studies were not 
required for the reference product, then these data generally would not be needed 
for licensure of a proposed biosimilar product under section 351(k) of the PHS 
Act.  However, if the BLA holder for the reference product has been required to 
conduct postmarket studies or clinical trials under section 505(o)(3) of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) to assess or identify a certain risk 
related to a QT/QTc study or a drug-drug interaction study and those studies have 
  9  Contains Nonbinding Recommendations 
not yet been completed, then FDA may impose similar postmarket requirements 
on the 351(k) applicant in appropriate circumstances.  
 
Q.I.10.  How long and in what manner should sponsors retain reserve samples of the 
biological products used in comparative clinical PK and/or PD studies intended 
to support a 351(k) application? 
[Final December 2018] 
 
A.I.10.  Reserve samples establish the identity of the products tested in the actual study, 
allow for confirmation of the validity and reliability of the results of the study, 
and facilitate investigation of further follow-up questions that arise after the 
studies are completed.  FDA recommends that the sponsor of a proposed 
biosimilar product retain reserve samples for at least 5 years following the date on 
which the 351(k) application is licensed, or, if such application is not licensed, at 
least 5 years following the date of completion of a comparative clinical PK and/or 
PD study of the reference product and the proposed biosimilar product (or other 
clinical study in which PK or PD samples are collected with the primary objective 
of assessing PK or PD similarity) that is intended to support a submission under 
section 351(k) of the PHS Act.  Contact FDA for specific advice if an alternative 
approach is being considered.  For a three-way PK similarity study, FDA 
recommends that samples of both comparator products be retained, in addition to 
samples of the proposed biosimilar product.   
 
For most protein therapeutics, FDA recommends that a sponsor retain the 
following quantities of product and dosage units, which are expected to be 
sufficient for evaluation by state of the art analytical methods:  
  Minimum of 10 dosage units each of the proposed biosimilar product, 
reference product and, if applicable, non-U.S.-licensed comparator product, 
depending on the amount of product within each unit; in general, this should 
provide for a total product mass of equal to or greater than 200 mg in a 
volume equal to or greater than 10 mL 
 
FDA recommends that the sponsor contact the review division to discuss the 
appropriate quantities of reserve samples in the following situations: 
  A product mass of equal to or greater than 200 mg in a volume equal to or 
greater than 10 mL requires a large number of dosage units 
  Biological products other than protein therapeutics 
 
* * * * * 
 
Q.I.11.  This question and its answer have been withdrawn.  For information on 
extrapolation, see FDAs guidance for industry Scientific Considerations in 
Demonstrating Biosimilarity to a Reference Product. 
 
* * * * * 
  10  Contains Nonbinding Recommendations 
 
Q.I.12.  This question and its answer have been retained in FDAs draft guidance for 
industry New and Revised Draft Q&As on Biosimilar Development and the 
BPCI Act (Revision 3).7   
 
* * * * * 
 
Q.I.13.  What constitutes publicly-available information regarding FDAs previous 
determination that the reference product is safe, pure, and potent to include in a 
351(k) application?  
[Final December 2018] 
 
A.I.13.  Publicly-available information in this context generally includes the current 
FDA-approved labeling for the reference product and the types of information 
found in the action package for a BLA (see section 505(l)(2)(C) of the FD&C 
Act).  However, FDA notes that submission of publicly available information 
composed of less than the current FDA-approved labeling for the reference 
product and the action package for the reference product BLA will generally not 
be considered a bar to submission or approval of an acceptable 351(k) application. 
 
FDA intends to post on the Agencys website publicly available information 
regarding FDAs previous determination of safety, purity, and potency for certain 
biological products to facilitate biosimilar development programs and submission 
of 351(k) applications.  We note, however, that the publicly available information 
posted by FDA in this context does not necessarily include all information that 
would otherwise be disclosable in response to a Freedom of Information Act 
request.  
 
Q.I.14.  Can an applicant obtain a determination of interchangeability between its 
proposed product and the reference product in an original 351(k) application?  
[Updated/Retained in Final September 2021] 
 
A.I.14.  Yes.  For more information, see FDAs guidance for industry Considerations in 
Demonstrating Interchangeability With a Reference Product, and Q&A I.26 in 
FDAs draft guidance for industry Biosimilarity and Interchangeability:  
Additional Draft Q&As on Biosimilar Development and the BPCI Act (November 
2020).8  
 
 
7 This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
8 This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
  11  Contains Nonbinding Recommendations 
Q.I.15.  Is a pediatric assessment under the Pediatric Research Equity Act (PREA) 
required for a proposed biosimilar product?  
[Updated/Retained in Final September 2021] 
 
A.I.15.  Under PREA (codified at section 505B of the FD&C Act), all applications for 
new active ingredients, new indications, new dosage forms, new dosing regimens, 
or new routes of administration are required to contain a pediatric assessment to 
support dosing and administration, safety, and effectiveness of the product for the 
claimed indication unless this requirement is waived, deferred, or inapplicable.9 
 
Under section 505B(l) of the FD&C Act,10 a biosimilar product that has not been 
determined to be interchangeable with the reference product is considered to have 
a new active ingredient for purposes of PREA, and a pediatric assessment is 
generally required unless waived or deferred or inapplicable.  Under the statute, 
an interchangeable product is not considered to have a new active ingredient for 
purposes of PREA.  However, if an applicant first seeks licensure of its proposed 
product as a biosimilar product, the applicant must address applicable PREA 
requirements for its noninterchangeable biosimilar product even if it ultimately 
intends to seek licensure of the product as an interchangeable product. 
 
See Q&A I.16 of this guidance for information on how a proposed biosimilar 
product applicant may fulfill the requirement for pediatric assessments under 
PREA. 
 
FDA encourages prospective biosimilar applicants to submit plans for pediatric 
studies as early as practicable during product development.  If there is no active 
investigational new drug (IND) application for the proposed biosimilar product 
and the sponsor intends to conduct a comparative clinical study as part of its 
development program, the initial pediatric study plan (PSP) should be submitted 
as a pre-IND submission.  In this scenario, FDA encourages the sponsor to meet 
with FDA before submission of the initial PSP to discuss the details of the 
planned development program.  A sponsor should submit the initial PSP before 
initiating any comparative clinical study in its biosimilar development program.  
For more information, see Q&A I.17 of this guidance.  See also the guidance for 
industry Pediatric Study Plans:  Content of and Process for Submitting Initial 
Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020). 
 
 
9 Section 505B(a)(1) was amended in 2017 by section 504 of the FDA Reauthorization Act of 2017 (Public Law 
115-52) (August 18, 2017) to include requirements for the submission of molecularly targeted pediatric cancer 
investigations for certain applications submitted on or after August 18, 2020, under section 505 of the FD&C Act or 
section 351 of the PHS Act.  These requirements are not specifically addressed in this Q&A. 
10 The statutory provision that appears in section 505B(l) of the FD&C Act was originally enacted as section 
505B(n) of the FD&C Act (as amended by the BPCI Act on March 23, 2010).  The provision was subsequently 
redesignated as 505B(m) of the FD&C Act.  See section 501(b) of the Food and Drug Administration Safety and 
Innovation Act (Public Law 112-144) (July 9, 2012).  The provision was redesignated again as section 505B(l).  See 
section 3102(3) of the 21st Century Cures Act (Public Law 114-255) (December 13, 2016). 
  12  Contains Nonbinding Recommendations 
Q.I.16.  How can a proposed biosimilar product applicant fulfill the requirement for 
pediatric assessments or investigations under PREA?  
[Moved to Final from Draft September 2021] 
 
A.I.16.  Applicants for proposed biosimilar products should address PREA requirements 
based upon the nature and extent of pediatric information in the reference product 
labeling.  As detailed below, PREA requirements are applicable to proposed 
biosimilar products that have not been determined to be interchangeable with a 
reference product only to the extent that compliance with PREA would not result 
in (1) a condition of use that has not been previously approved for the reference 
product; or (2) a dosage form, strength, or route of administration that differs 
from that of the reference product. 
 
As a preliminary matter, there are differences in the use of the term extrapolation 
in the context of a proposed biosimilar product under the PHS Act and in the 
context of PREA: 
  An applicant may provide scientific justification for extrapolation to support 
approval of a biosimilar product under section 351(k) of the PHS Act for one 
or more conditions of use.  For more information on extrapolation in this 
context, see FDAs guidance for industry Scientific Considerations in 
Demonstrating Biosimilarity to a Reference Product.  
  Pediatric extrapolation refers to an approach to providing evidence to 
establish the effectiveness of a drug in a pediatric population when it can be 
assumed that the course of the disease and the expected response to a 
medicinal product would be sufficiently similar in the pediatric and reference 
(adult or other pediatric) population.11 
 
In the discussion that follows, the term extrapolation generally is used to refer to 
extrapolation to support approval of a biosimilar product under section 351(k) of 
the PHS Act for one or more conditions of use, and not to pediatric extrapolation: 
  Adequate pediatric information in reference product labeling.  If the labeling 
for the reference product contains adequate pediatric information (e.g., 
information reflecting an adequate pediatric assessment): 
  If the biosimilar applicant seeks licensure in adults for an indication for 
which the reference product is approved for pediatric use, a biosimilar 
applicant may fulfill its PREA requirements for that indication by 
satisfying the statutory requirements for demonstrating biosimilarity and 
providing adequate scientific justification under the BPCI Act to support 
extrapolation of data and information to support licensure.  If the 
submitted scientific justification for extrapolation is inadequate, a 
 
11 Guidance for industry E11(R1) Addendum:  Clinical Investigation of Medicinal Products in the Pediatric 
Population (April 2018).  See also sections 505B(a)(2)(B) and 505B(a)(3)(B) of the FD&C Act. 
  13  Contains Nonbinding Recommendations 
biosimilar applicant must submit appropriate data to fulfill applicable 
PREA requirements.  
  If the reference product is not approved for pediatric use but its labeling 
includes pediatric information (e.g., where a pediatric study was 
conducted but failed to meet the requirements for licensure of a pediatric 
indication but information is included in the reference product labeling), 
the biosimilar applicant may fulfill PREA requirements for that indication 
by including the relevant pediatric information in its labeling.   
  Lack of adequate pediatric information in reference product labeling: 
  If the labeling for the reference product does not contain adequate 
pediatric information for one or more pediatric age groups for an 
indication for which a biosimilar applicant seeks licensure in adults, and 
applicable PREA requirements were deferred for the reference product for 
those pediatric age groups, a biosimilar applicant should request a deferral 
of PREA requirements for those pediatric age groups.  Once the reference 
product labeling is updated with relevant pediatric information, the 
biosimilar applicant should amend or supplement its 351(k) BLA, as 
appropriate, to seek approval for updated labeling, supported by 
extrapolation or appropriate data. 
  If the labeling for the reference product does not contain adequate 
pediatric information for one or more pediatric age groups for an 
indication for which a biosimilar applicant seeks licensure in adults, and 
PREA requirements were waived for, or inapplicable to, the reference 
product for those pediatric age groups, a biosimilar applicant should note 
this information, if any, in its initial PSP, but it does not need to request a 
waiver of PREA requirements for those age groups.  For proposed 
biosimilars, obligations under PREA are circumscribed by the BPCI Act 
to require an assessment only for indications and age groups or other 
conditions of use in which the reference product has been or will be 
assessed.  In other words, the Agency has determined that PREA 
requirements are applicable to a proposed biosimilar product that has not 
been determined to be interchangeable with a reference product only to the 
extent that compliance with PREA would not result in (1) a condition of 
use that has not been previously approved for the reference product, or (2) 
a dosage form, strength, or route of administration that differs from that of 
the reference product. 
 
FDAs recommendations to biosimilar applicants with respect to the PREA 
requirements reflect a clarification based on the Agencys interpretation of the 
interaction between section 505B of the FD&C Act (PREA) and section 351(k) of 
the PHS Act.  Biosimilar applicants previously requested, and the Agency 
granted, waivers in instances where PREA requirements were waived for or 
determined to be inapplicable to the reference product.  However, upon further 
consideration, waivers for biosimilars applicants under those circumstances were 
  14  Contains Nonbinding Recommendations 
not necessary, and the practice is more accurately described in terms of the 
Agencys interpretation of the BPCI Act and PREA.  The BPCI Act added section 
351(k) of the PHS Act and amended section 505B of the FD&C Act to specify 
that PREA is applicable to a biosimilar product that has not been determined to be 
interchangeable with a reference product (see section 7002(a), (d)(2) of the BPCI 
Act).  FDA reads section 351(k) of the PHS Act and PREA together with respect 
to conducting assessments of and seeking licensure for certain pediatric uses and 
pediatric formulations. 
 
An application submitted under section 351(k) of the PHS Act must include, 
among other things, information demonstrating that the condition or conditions 
of use prescribed, recommended, or suggested in the labeling proposed for the 
biological product have been previously approved for the reference product and 
the route of administration, the dosage form, and the strength of the biological 
product are the same as those of the reference product (section 
351(k)(2)(A)(i)(III)-(IV) of the PHS Act).  FDA has determined that, when the 
reference product does not have adequate pediatric use information in its labeling 
or an age-appropriate formulation for a relevant pediatric population, the 
obligations for the biosimilar applicant under PREA are circumscribed by section 
351(k) of the PHS Act.  Specifically, the biosimilar applicant would not be 
expected to obtain licensure for a pediatric use (or describe that use in product 
labeling) that has not been licensed for the reference product and would not be 
expected to obtain licensure of a product that would result in a dosage form, 
strength, or route of administration that differs from that of the reference product.   
 
By establishing an abbreviated licensure pathway for biosimilar and 
interchangeable products, the BPCI Act reflects the strong public health interest in 
the licensure and availability of those products.  Such licensure could result in 
increased competition, as well as greater access to biological products.  The 
Agencys interpretation of section 351(k) and PREA assures that biosimilar 
applicants are not subject to greater regulatory burdens than those faced by 
reference product sponsors with respect to the study of pediatric uses. 
 
This approach preserves the intent and availability of an abbreviated licensure 
pathway for biosimilars while helping to ensure that a biosimilar product is 
labeled and formulated for relevant pediatric conditions of use that have been 
approved for the reference product.  FDA also recognizes the important interests 
furthered by PREA and appreciates the need to study pediatric uses of biological 
products and to include pediatric use information in product labeling.  
Consequently, in appropriate cases, FDA may take additional steps within its 
authority to assure that pediatric use information is included in biological product 
labeling.12  Such actions may include invoking the marketed drugs provision 
 
12 For instance, if the Agency determines that the basis for the reference products waiver under PREA no longer 
applies to a particular age group (e.g., because it is now feasible to study a younger pediatric age group), FDA may, 
as appropriate, contact the 351(k) biosimilar product sponsor, as well as the reference product sponsor, and require 
further action by both parties to comply with PREA.  See section 505B(a)(5) of the FD&C Act. 
  15  Contains Nonbinding Recommendations 
under PREA, in certain circumstances, to require sponsors to conduct pediatric 
assessments, or take other appropriate steps, to support pediatric labeling for both 
the biosimilar product and the reference product.13 
 
If a biosimilar applicant believes that none of the situations described above apply 
to its proposed product, the applicant should contact FDA for further information.  
 
Q.I.17.  When should a proposed biosimilar product applicant submit an initial 
pediatric study plan (PSP)?  
[Updated/Retained in Final September 2021] 
 
A.I.17.  Section 505B(e) of the FD&C Act requires applicants subject to PREA to submit 
an initial pediatric study plan (PSP) before the date on which the applicant 
submits the required assessments or investigation, and no later than 60 calendar 
days after the date of an end-of-phase 2 (EOP2) meeting or at such other time as 
agreed upon by FDA and the applicant.  FDA has issued guidance on the PSP 
process, including the timing of PSP submission.14  
 
Sections 505B(e)(2)(C) and 505B(e)(3) of the FD&C Act set forth a process for 
reaching agreement between an applicant and FDA on an initial PSP that 
generally lasts up to 210 days.  Given the potential length of this process, and in 
the absence of an EOP2 meeting for a proposed biosimilar product, FDA 
recommends that if a sponsor has not already initiated a comparative clinical 
study intended to address the requirements under section 351(k)(2)(A)(i)(I)(cc) of 
the PHS Act, the sponsor should submit an initial PSP as soon as feasible, but no 
later than 210 days before initiating such a study.  This is intended to provide 
adequate time to reach agreement with FDA on the initial PSP before the study is 
initiated.  Depending on the details of the clinical program, it may be appropriate 
to submit an initial PSP earlier in development.  FDA encourages the sponsor to 
meet with FDA to discuss the details of the planned development program before 
submission of the initial PSP.   
 
For additional information on submission of the PSP, including a PSP template, 
please refer to: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/ucm049867.htm.  After the initial PSP is submitted, FDA and the sponsor work 
to reach timely agreement on the plan; this process is set forth in section 
505B(e)(2)-(3) of the FD&C Act.  FDA does not formally grant or deny a request 
for a waiver or deferral in response to the initial PSP.   
 
 
13 See section 505B(b) of the FD&C Act. 
14 See the guidance for industry Pediatric Study Plans:  Content of and Process for Submitting Initial Pediatric 
Study Plans and Amended Initial Pediatric Study Plans (July 2020).   
  16  Contains Nonbinding Recommendations 
Q.I.18.  For biological products intended to be injected, how can an applicant 
demonstrate that its proposed biosimilar product has the same dosage form as 
the reference product? 
[Final December 2018] 
 
A.I.18.  Under section 351(k)(2)(A)(i)(IV) of the PHS Act, an applicant must demonstrate 
that the dosage form of the proposed biosimilar or interchangeable product is 
the same as that of the reference product.  For purposes of implementing this 
statutory provision, FDA considers the dosage form to be the physical 
manifestation containing the active and inactive ingredients that delivers a dose of 
the drug product.  In the context of proposed biosimilar products intended to be 
injected, FDA considers, for example, injection (e.g., a solution) to be a 
different dosage form from for injection (e.g., a lyophilized powder).  Thus, if 
the dosage form of the reference product is injection, an applicant could not 
obtain licensure of a proposed biosimilar product with a dosage form of for 
injection even if the applicant demonstrated that the proposed biosimilar product, 
when constituted or reconstituted, could meet the other requirements for an 
application for a proposed biosimilar product. 
 
For purposes of section 351(k)(2)(A)(i)(IV) of the PHS Act, FDA also considers 
emulsions and suspensions of products intended to be injected to be distinct 
dosage forms.  Liposomes, lipid complexes, and products with extended-release 
characteristics present special scenarios due to their unique composition, and 
prospective applicants seeking further information should contact FDA.   
 
It should be noted, however, that this interpretation regarding the same dosage 
form is for purposes of section 351(k)(2)(A)(i)(IV) of the PHS Act only.  For 
example, this interpretation should not be cited by applicants seeking approval of 
a new drug application under section 505(c) of the FD&C Act, approval of an 
abbreviated new drug application under section 505(j) of the FD&C Act, or 
licensure of a BLA under section 351(a) of the PHS Act for purposes of 
determining whether separate applications should be submitted and assessed 
separate fees for different dosage forms. 
 
Q.I.19.  If a non-U.S.-licensed product is proposed for importation and use in the 
United States in a clinical investigation intended to support licensure of a 
proposed product under section 351(k) (e.g., a bridging clinical PK and/or PD 
study), is a separate IND required for the non-U.S.-licensed product? 
[Updated/Retained in Final September 2021] 
 
A.I.19.  A sponsor may submit a single IND application for a development program that is 
intended to support licensure of a proposed product under section 351(k) of the 
PHS Act and includes use of a non-U.S.-licensed product.  The sponsor should 
submit information supporting the proposed clinical investigation with the non-
U.S.-licensed comparator product under the IND application.  This scenario may 
occur, for example, if a sponsor seeks to use data from a clinical study comparing 
  17  Contains Nonbinding Recommendations 
its proposed biosimilar product to a non-U.S.-licensed product to address, in part, 
the requirements under section 351(k)(2)(A) of the PHS Act, and proposes to 
conduct a clinical PK study, with PD data, as appropriate, in the United States 
with all three products (i.e., the proposed biosimilar product, the U.S.-licensed 
reference product, and the non-U.S.-licensed product) to support establishment of 
a bridge between all three products and scientific justification for the relevance of 
these comparative data to an assessment of biosimilarity to the U.S.-licensed 
reference product. 
 
A non-U.S.-licensed comparator product is considered an investigational new 
drug in the United States, and thus would require an IND application for 
importation and use in the United States (see 21 CFR 312.110(a)).  If a sponsor 
intends to conduct a clinical investigation in the United States using a non-U.S.-
licensed comparator product, the IND requirements in 21 CFR part 312 also 
would apply to this product (see, e.g., 21 CFR 312.2). 
 
With respect to chemistry, manufacturing, and controls (CMC) information, a 
sponsor should submit to the IND application as much of the CMC information 
required by 21 CFR 312.23(a)(7) as is available.  However, FDA recognizes that a 
sponsor may not be able to obtain all of the CMC information required by 21 CFR 
312.23(a)(7) for a non-U.S.-licensed comparator product for which it is not the 
manufacturer.  In these circumstances, the sponsor can request in an IND 
submission that FDA waive the regulatory requirements related to CMC 
information on the non-U.S.-licensed comparator product (21 CFR 312.10).  The 
waiver request must include at least one of the following: 
  An explanation why compliance with the requirements of 21 CFR 
312.23(a)(7) is unnecessary or cannot be achieved 
  Information that will satisfy the purpose of the requirement by helping to 
ensure that the investigational new drug will have the proper identity, 
strength, quality, and purity 
  Other information justifying a waiver15 
 
Information that is relevant to whether the investigational new drug will have the 
proper identity, strength, quality, and purity may include, for example, 
information indicating whether the investigational new drug has been licensed by 
a regulatory authority that has similar scientific and regulatory standards as FDA 
(e.g., ICH countries).  This should include, to the greatest extent possible, 
summary approval information and current product labeling made public by the 
foreign regulatory authority.  In addition, a sponsor should also provide 
information on the conditions and containers that will be used to transport the 
drug product to the U.S. clinical site(s) and information on the relabeling and 
repackaging operations that will be used to relabel the drug product vials for 
 
15 See 21 CFR 312.10(a). 
  18  Contains Nonbinding Recommendations 
investigational use.  This should include information on how exposure of the 
product to light and temperature conditions outside of the recommended storage 
conditions will be prevented.  A risk assessment on the impact the relabeling 
operations may have on drug product stability should also be included. 
 
The sponsor should consult with the appropriate FDA review division regarding 
the CMC information necessary to support the proposed clinical study.  
 
As would be applicable to all investigational new drugs, FDA reminds sponsors 
that the investigator brochure (IB) for studies to be conducted under the IND 
application should be carefully prepared to ensure that it is not misleading, 
erroneous, or materially incomplete, which can be a basis for a clinical hold (see 
21 CFR 312.42(b)(1)(iii) and (b)(2)(i)).  For example, the term reference product 
should be used in the IB only to refer to the single biological product licensed 
under section 351(a) of the PHS Act against which the proposed product is 
evaluated for purposes of submitting a 351(k) application. 
 
The IB and study protocol(s) should use consistent nomenclature that clearly 
differentiates the proposed product from the reference product.  Additionally, the 
IB and study protocol(s) should both clearly describe whether the comparator 
used in each study is the U.S.-licensed reference product or a non-U.S.-licensed 
comparator product and use consistent nomenclature that clearly differentiates 
these products.  If a non-U.S.-licensed comparator product is being used in a 
study conducted in the United States, the IB and study protocol(s) should clearly 
convey that the product is not FDA-approved and is considered an investigational 
new drug in the United States.  The IB and study protocol(s) also should avoid 
conclusory statements regarding regulatory determinations (e.g., comparable, 
biosimilar, interchangeable, highly similar) that have not been made.  
 
Q.I.20.  What is the nature and type of information that a sponsor should provide to 
support a postapproval manufacturing change for a licensed biosimilar 
product? 
[Moved to Final from Draft September 2021] 
 
A.I.20.  In general, similar to manufacturing changes under section 351(a) of the PHS Act, 
a sponsor that intends to make a manufacturing change to a licensed biosimilar 
product should follow the principles outlined in the ICH guidance for industry 
Q5E Comparability of Biotechnological/Biological Products Subject to Changes 
in their Manufacturing Process (June 2005).  Accordingly, the sponsor should 
provide sufficient data and information to demonstrate the comparability of the 
biosimilar product before and after the manufacturing change.  The comparability 
assessment should include (1) side-by-side analytical comparison of a sufficient 
number of lots of prechange and postchange material, including stability data, as 
appropriate; and (2) comparison of analytical data from the postchange material to 
historical analytical data from biosimilar lots used in the analytical similarity 
assessment, including data from lots used in clinical studies that supported 
  19  Contains Nonbinding Recommendations 
licensure of the biosimilar product.  A well-qualified, in-house reference standard 
should also be included in the comparability exercise.  In certain cases, additional 
reference materials, such as an international reference standard or a specific 
impurity reference material, may be included in the comparability study.  The 
extent of data and information necessary to establish comparability would be 
commensurate with the type of manufacturing change and its potential impact on 
product quality, safety, and efficacy. 
 
In addition, FDA continues to consider the nature and type of information a 
sponsor should provide to support a postapproval manufacturing change to a 
biological product determined by FDA to be interchangeable with the reference 
product under section 351(k)(4) of the PHS Act.  FDA intends to provide specific 
recommendations for postapproval manufacturing changes to interchangeable 
biological products in future guidance.   
 
A sponsor may seek approval, in a supplement to an approved 351(k) BLA, of a 
route of administration, a dosage form, or a strength that is the same as that of the 
reference product, but that has not previously been licensed under the 351(k) 
BLA.16  FDA intends to provide specific recommendations on this topic in future 
guidance. 
 
Q.I.21.  May a sponsor seek approval, in a 351(k) application or a supplement to an 
approved 351(k) BLA, of a route of administration, a dosage form, or a strength 
that is different from that of the reference product?  
[Moved to Final from Draft September 2021] 
 
A.I.21.  No.  Under section 351(k)(2)(A)(i)(IV) of the PHS Act, a 351(k) application must 
include information demonstrating that the route of administration, the dosage 
form, and the strength of the proposed biosimilar or interchangeable product are 
the same as those of the reference product.  An applicant may not seek approval, 
in a 351(k) application or a supplement to an approved 351(k) application, for a 
route of administration, a dosage form, or a strength that is different from that of 
the reference product. 
 
 
16 As described elsewhere in this guidance (Q&A I.21), a 351(k) applicant may not seek approval of a route of 
administration, a dosage form, or a strength that is different from the reference product, including in a supplement to 
an approved 351(k) application.  See Q&A I.21 and the draft guidance for industry Biosimilars and Interchangeable 
Biosimilars:  Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed 
(Licensure for Fewer than All Conditions of Use Guidance) (February 2020) for additional information.  This draft 
guidance, when finalized, will represent FDAs current thinking on this topic. 
  20  Contains Nonbinding Recommendations 
Q.I.22.  May a sponsor seek approval, in a 351(k) application or a supplement to an 
approved 351(k) BLA, for a condition of use that has not previously been 
approved for the reference product?  
[Moved to Final from Draft September 2021] 
 
A.I.22.  No.  Under section 351(k)(2)(A)(i)(III) of the PHS Act, the 351(k) application 
must include information demonstrating that the condition or conditions of use 
prescribed, recommended, or suggested in the labeling proposed for the proposed 
biosimilar or interchangeable product have been previously approved for the 
reference product.  A 351(k) applicant may not seek approval, in a 351(k) 
application or a supplement to an approved 351(k) application, of a condition of 
use (e.g., indication, dosing regimen) that has not been previously approved for 
the reference product.   
 
Whether an applicant is seeking licensure of a proposed biosimilar product for 
allor fewer than allof the conditions of use licensed for the reference product 
affects which data and information from the reference product labeling should be 
incorporated into the proposed biosimilar labeling.17 
 
* * * * * 
 
Q.I.23.  This question and its answer have been withdrawn.   
 
* * * * * 
 
Q.I.24.  May an applicant submit data and information to support approval of a 
proposed biosimilar or interchangeable product for an indication for which the 
reference product has unexpired orphan exclusivity?  
[Moved to Final from Draft September 2021] 
 
 
A.I.24.  When an applicant is seeking licensure for an indication for which the reference 
product has unexpired orphan exclusivity, an applicant should submit data and 
information to support approval of a proposed biosimilar or interchangeable 
product for this indication.18  For example, an applicant may submit data and 
 
17 For additional information, see FDAs guidance for industry Labeling for Biosimilar Products.  As also stated in 
that guidance, FDA recommends that labeling for a biosimilar product incorporate relevant data and information 
from the reference product labeling, with appropriate modifications.  Additionally, FDAs draft guidance for 
industry Biosimilars and Interchangeable Biosimilars:  Licensure for Fewer Than All Conditions of Use for Which 
the Reference Product Has Been Licensed, states that although biosimilar labeling need not be identical to reference 
product labeling, deviations should be carefully considered to ensure that the condition or conditions of use 
prescribed, recommended, or suggested in the draft labeling for the proposed biosimilar product have been 
previously approved for the reference product (see section 351(k)(2)(A)(i)(III) of the PHS Act).  This draft 
guidance, when finalized, will represent FDAs current thinking on this topic. 
18 As stated in FDAs guidance for industry Considerations in Demonstrating Interchangeability With a Reference 
Product (May 2019), FDA expects that applicants seeking to demonstrate interchangeability will submit data and 
information to support a showing that the proposed interchangeable product can be expected to produce the same 
 
  21  Contains Nonbinding Recommendations 
information intended to provide sufficient scientific justification for extrapolation 
to support approval of a proposed biosimilar or interchangeable product for one or 
more indications, including an indication(s) for which the reference product has 
unexpired orphan exclusivity.  In reviewing such information under section 
351(k), FDA will not approve the proposed product for the protected 
indication(s).19    
 
II. PROVISIONS RELATED TO REQUIREMENT TO SUBMIT A BLA FOR A 
BIOLOGICAL PRODUCT 
 
Q.II.1.  This question and its answer have been withdrawn.  For information on the 
definition of protein in section 351(i)(1) of the PHS Act, see Final Rule on 
Definition of the Term Biological Product (85 FR 10057, February 21, 
2020) and 21 CFR 600.3(h)(6). 
  
* * * * * 
 
Q.II.2.  How is product class defined for purposes of determining whether an 
application for a biological product may be submitted under section 505 of the 
FD&C Act during the transition period? 
[Final April 2015] 
 
A.II.2.  For purposes of section 7002(e)(2) of the ACA, a proposed biological product 
will be considered to be in the same product class as a protein product previously 
approved under section 505 of the FD&C Act on or before March 23, 2010, if 
both products are homologous to the same gene-coded sequence (e.g., the INS 
gene for insulin and insulin glargine) with allowance for additional novel flanking 
sequences (including sequences from other genes).  Products with discrete 
changes in gene-coded sequence or discrete changes in post-translational 
modifications may be in the same product class as the previously approved 
product even if the result may be a change in product PK.  
 
For naturally derived protein products that do not have identified sequences 
linked to specific genes and that were approved under section 505 of the FD&C 
Act on or before March 23, 2010, a proposed biological product is in the same 
product class as the naturally derived protein product if both products share a 
primary biological activity (e.g., the 4-number Enzyme Commission code for 
enzyme activity). 
 
 
clinical result as the reference product in all of the reference products licensed conditions of use.  We update 
guidances periodically.  For the most recent version of a guidance, check the FDA Drugs guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
19 See Licensure for Fewer than All Conditions of Use Guidance for information about timing of submissions for 
supplements seeking licensure for indications protected by unexpired exclusivity.  This draft guidance, when 
finalized, will represent FDAs current thinking on this topic. 
  22  Contains Nonbinding Recommendations 
However, for any protein product (whether naturally derived or otherwise), if the 
difference between the proposed product and the protein product previously 
approved under section 505 of the FD&C Act alters a biological target or effect, 
the products are not in the same product class for purposes of section 7002(e)(2) 
of the ACA.  
 
Q.II.3.  What type of marketing application should be submitted for a proposed 
antibody-drug conjugate? 
[Final December 2018] 
 
A.II.3.  A BLA should be submitted for a proposed monoclonal antibody that is linked to 
a drug (antibody-drug conjugate).  FDA considers an antibody-drug conjugate to 
be a combination product composed of a biological product constituent part and a 
drug constituent part (see 21 CFR 3.2(e)(1); 70 FR 49848, 4985749858 (August 
25, 2005)). 
 
CDER is the FDA center assigned to regulate antibody-drug conjugates, 
irrespective of whether the biological product constituent part or the drug 
constituent part is determined to have the primary mode of action.  For more 
information, see section 503(g) of the FD&C Act; see also, e.g., Transfer of 
Therapeutic Biological Products to the Center for Drug Evaluation and Research 
(June 30, 2003), available at 
https://www.fda.gov/CombinationProducts/JurisdictionalInformation/ucm136265.
htm; Intercenter Agreement Between the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research (October 31, 
1991), available at 
https://www.fda.gov/CombinationProducts/JurisdictionalInformation/ucm121179.
htm. 
 
To enhance regulatory clarity and promote consistency, CDER considered several 
factors to determine the appropriate marketing application type for antibody-drug 
conjugates, including the relative significance of the safety and effectiveness 
questions raised by the constituent parts, particularly the highly specific molecular 
targeting by the antibody to a cell type, cellular compartment, or other marker at 
the site of action (as distinguished from mere alteration of systemic PK). 
 
In light of such factors, CDER considers submission of a BLA under section 351 
of the PHS Act to provide the more appropriate application type for antibody-drug 
conjugates. 
 
Sponsors seeking to submit a BLA for a proposed antibody-drug conjugate may 
contact CDERs Office of New Drugs at 301-796-0700 for further information.  
 
 
  23  Contains Nonbinding Recommendations 
III. EXCLUSIVITY 
 
Q.III.1.  Can an applicant include in its 351(a) BLA submission a request for reference 
product exclusivity under section 351(k)(7) of the PHS Act? 
[Final December 2018] 
 
A.III.1.  Yes.  An applicant may include in its BLA submission a request for reference 
product exclusivity under section 351(k)(7) of the PHS Act, and FDA will 
consider the applicants assertions regarding the eligibility of its proposed product 
for exclusivity.  For more information, see FDAs draft guidance for industry 
Reference Product Exclusivity for Biological Products Filed Under Section 
351(a) of the PHS Act.20  The draft guidance describes the types of information 
that reference product sponsors should provide to facilitate FDAs determination 
of the date of first licensure for their products.   
 
Q.III.2.  How can a prospective biosimilar applicant determine whether there is 
unexpired orphan exclusivity for an indication for which the reference product 
is licensed? 
[Updated/Retained in Final September 2021] 
 
A.III.2.  The FDAs Orphan Drug Product designation database is available to search for 
orphan drug designations and/or approvals.  The database is updated monthly (see 
https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm).  FDA will not 
approve a subsequent application for the same drug for the same indication during 
the 7-year period of orphan exclusivity, except as otherwise provided in the 
FD&C Act and 21 CFR part 316.   
 
 
20 This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
  24