Questions and Answers on Biosimilar Development and the BPCI Act: Guidance for Industry

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

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)
October 2026
Biosimilars
Revision 4

Questions and Answers on
Biosimilar Development and
the BPCI Act
Guidance for Industry
Additional copies are available from:
Office of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
Phone: 855-543-3784 or 301-796-3400
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drug s
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
Phone: 800-835-4709 or 240-402-8010
Email: industry.biologics@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)
October 2026
Biosimilars
Revision 4

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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? .................................................................................................................................. 4
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?............................................... 6
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? .......................................................................... 7
Q.I.13. What constitutes “publicly-available information” regarding FDA’s previous
determination that the reference product is safe, pure, and potent to include in a
351(k) application? ....... ………………………………………………………………………………8
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?................................... 8
Q.I.15. Is a pediatric assessment under the Pediatric Research Equity Act (PREA) required for
a proposed biosimilar product? .............................................................................................. 9
Q.I.16. How can a proposed biosimilar product applicant fulfill the requirement for pediatric
assessments or investigations under PREA? ......................................................................... 10

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Q.I.17. When should a proposed biosimilar product applicant submit an initial pediatric study
plan (PSP)? ........................................................................................................................... 13
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? ........ 14
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? ............................................................................................... 15
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? .. …………………………………………………………………………………15
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? ........................................................................................ 16
II. PROVISIONS RELATED TO REQUIREMENT TO SUBMIT A BLA FOR A
“BIOLOGICAL PRODUCT” ....................................................................................................... 16
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?……………………………………………………………………………………17
Q.II.3. What type of marketing application should be submitted for a proposed antibody-drug
conjugate? ............................................................................................................................. 17
III. EXCLUSIVITY .............................................................................................................................. 18
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? ............................................................. 18
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?............... 18

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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 provides answers to common questions from prospective applicants and other
interested parties regarding section 351(k) of the Public Health Service Act (PHS Act) (42
U.S.C. 262(k)), which was added by 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 biosimilar products and proposed
interchangeable biosimilar products,2 as well as describe FDA’s interpretation of certain
statutory requirements.
Section 351(k) of the PHS Act provides an abbreviated licensure pathway 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 (Public Law
111-148) (ACA)). FDA believes that guidance for industry that provides answers to commonly
asked questions regarding FDA’s interpretation of section 351(k) of the PHS 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
prospective applicants regarding the submission of biologics license applications (BLAs) for
1 This guidance has been prepared by the Center for Drug Evaluation and Research and the Center for Biologics
Evaluation and Research at the Food and Drug Administration. You may submit comments on this guidance any time.
Submit comments to Docket No. FDA-2011-D-0611 (available at https://www.regulations.gov/docket?D=FDA-2011-
D-0611). See the instructions in that docket for submitting comments on this and other Level 2 guidance updates.
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 section 351(i)(2) and (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 section 351(i)(3) and (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.

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biosimilar and interchangeable products. FDA intends to update this final guidance to include
additional Q&As as appropriate.
This final guidance is part of a series of guidance documents that FDA developed to facilitate
development of biosimilar and interchangeable biosimilar products. It revises and replaces the
guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act
(September 2021) (Revision 2).
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
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
(see sections 7001 through 7003 of the ACA). Section 351(k) of the PHS Act added by the
BPCI Act, sets forth the requirements for the licensure of a proposed biosimilar or proposed
interchangeable biosimilar product.
Section 351(i) of the PHS Act 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, an assessment of toxicity, and a clinical study or
studies (see section 351(k)(2)(A)(i)(I) of the PHS Act), unless FDA has determined that an
element described in section 351(k)(2)(A)(i)(I) is unnecessary (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).

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“Question and Answer” Guidance Format
FDA has been using the Q&A guidance format to describe the Agency’s thinking on and update
certain information and recommendations relevant to the development of biosimilar and
interchangeable products. This guidance includes all Q&As that are in final form. The draft
guidance for industry Biosimilarity and Interchangeability: Additional Draft Q&As on
Biosimilar Development and the BPCI Act) (September 2023) (Revision 1) (Additional Draft
Q&A guidance) and the draft guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 4) (March 2026)3 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, if warranted, incorporated suggested changes to the
Q&A, individual Q&As will be moved to the final guidance, as appropriate.
A Q&A that was previously in the final guidance may be withdrawn and moved to a draft
guidance if FDA determines that the Q&A should be revised in some respect and reissued in a
revised draft Q&A for comment. A Q&A also may be withdrawn and removed from the Q&A
guidance if, for instance, the issue addressed in the Q&A is addressed in another FDA guidance.
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 guidance for industry
Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2), the draft
guidance for industry New and Revised Draft Q&As on Biosimilar Development and the BPCI
Act (Revision 3) (September 2021)4 (New and Revised Draft Q&A guidance), 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 to the final guidance and, where appropriate, when a Q&A is withdrawn
from the final guidance and moved to a draft guidance. 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, the final guidance will clearly identify the draft guidance in which the Q&As were
issued.
When FDA withdraws a Q&A or moves it from draft guidance to final guidance or from final
guidance to draft guidance for public comment, it marks the change in the first guidance with
several asterisks between nonconsecutive Q&As and provides explanatory text when
appropriate.
3 When final, this guidance will represent FDA’s current thinking on this topic. For the most recent version of a
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.
4 When final, this guidance will represent FDA’s current thinking on this topic.

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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 FDA’s draft guidance for industry Formal Meetings Between the FDA and
Sponsors or Applicants of BsUFA Products,5 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
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 FDA’s current thinking on
the interpretation of the statutory standard for biosimilarity, see FDA’s guidance
for industry Scientific Considerations in Demonstrating Biosimilarity to a
5 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.

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Reference Product, and draft guidance for industry Development of Therapeutic
Protein Biosimilars: Comparative Analytical Assessment and Other Quality-
Related Considerations.6
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
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.
6 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.

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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
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).

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For information about the licensure of a proposed interchangeable product, see
FDA’s guidance for industry Considerations in Demonstrating Interchangeability
With a Reference Product.7
* * * * *
Q.I.8. 	This question and its answer have been revised and retained in FDA’s draft
guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 4).
* * * * *
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 Agency’s 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
not yet been completed, then FDA may impose similar postmarket requirements
on the 351(k) applicant in appropriate circumstances.
* * * * *
Q.I.10. 	This question and its answer have been revised and retained in FDA’s draft
guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 4).
* * * * *
7 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 product’s licensed conditions of use.

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Q.I.11. 	This question and its answer have been withdrawn. For information on
extrapolation, see FDA’s guidance for industry Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product.
* * * * *
Q.I.12. 	This question and its answer have been retained in FDA’s draft guidance for
industry New and Revised Draft Q&As on Biosimilar Development and the
BPCI Act (Revision 4).8
* * * * *
Q.I.13. 	What constitutes “publicly-available information” regarding FDA’s 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 Agency’s website publicly available information
regarding FDA’s 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 FDA’s guidance for industry Considerations in
Demonstrating Interchangeability With a Reference Product, and Q&A I.26 in
FDA’s draft guidance for industry Biosimilarity and Interchangeability:
Additional Draft Q&As on Biosimilar Development and the BPCI Act (November
2020).9
8 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.
9 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.

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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.10
Under section 505B(l) of the FD&C Act,11 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).
10 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.
11 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).

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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 FDA’s 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.”12
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
12 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.

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submitted scientific justification for extrapolation is inadequate, a
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.
FDA’s recommendations to biosimilar applicants with respect to the PREA
requirements reflect a clarification based on the Agency’s 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

Contains Nonbinding Recommendations
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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
not necessary, and the practice is more accurately described in terms of the
Agency’s 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
Agency’s 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

Contains Nonbinding Recommendations
13
labeling.13 Such actions may include invoking the “marketed drugs” provision
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.14
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.15
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
13 For instance, if the Agency determines that the basis for the reference product’s 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.
14 See section 505B(b) of the FD&C Act.
15 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).

Contains Nonbinding Recommendations
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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.
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. 	This question and its answer have been revised and retained in FDA’s draft
guidance for industry New and Revised Draft Q&As on Biosimilar
Development and the BPCI Act (Revision 4).
* * * * *
Q.I.20. 	This question and its answer have been withdrawn. For information on
postapproval manufacturing changes, see FDA’s guidance for industry

Contains Nonbinding Recommendations
15
Postapproval Manufacturing Changes to Biosimilar and Interchangeable
Biosimilar Products Questions and Answers.
* * * * *
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.
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
all—or fewer than all—of 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.16
16 For additional information, see FDA’s 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, FDA’s 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 FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
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* * * * *
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.17 For example, an applicant may submit data and
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).18
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).
* * * * *
17 As stated in FDA’s 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
clinical result as the reference product in all of the reference product’s 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.
18 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 FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
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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).
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, 49857–49858 (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

Contains Nonbinding Recommendations
18
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 CDER’s Office of New Drugs at 301-796-0700 for further information.
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 applicant’s assertions regarding the eligibility of its proposed product
for exclusivity. For more information, see FDA’s draft guidance for industry
Reference Product Exclusivity for Biological Products Filed Under Section
351(a) of the PHS Act.19 The draft guidance describes the types of information
that reference product sponsors should provide to facilitate FDA’s 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 FDA’s 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
19 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.

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the 7-year period of orphan exclusivity, except as otherwise provided in the
FD&C Act and 21 CFR part 316.

Contains Nonbinding Recommendations
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Guidance History * 	Date 	Description
Level 2 Final Guidance –
Revision 4
October 2026 See notice of availability for “Postapproval
Manufacturing Changes to Biosimilar and
Interchangeable Biosimilar Products: Questions and
Answers; Guidance for Industry; Availability”
(October 2026) for more information**
Level 2 Final Guidance –
Revision 3
March 2026 	See notice of availability for “New and Revised Draft
Q&As on Biosimilar Development and the Biologics
Price Competition and Innovation Act; Draft Guidance
for Industry; Availability” (March 2026) for more
information**
* This table was implemented beginning October 2026, and previous guidance history may not
be captured in totality.
** The notice of availability is accessible via the Search for FDA Guidance Documents web
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.