Interpretation of the  
Deemed to be a License Provision of 
the Biologics Price Competition and 
Innovation Act of 2009 
 
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) 
 
December 2018  
Procedural 
   
Interpretation of the  
Deemed to be a License Provision of 
the Biologics Price Competition and 
Innovation Act of 2009 
 
Guidance for Industry 
 
 
Additional copies are available from: 
 
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Food and Drug Administration 
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and/or 
 
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Email: ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
December 2018  
Procedural 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  BPCI Act ............................................................................................................................ 2 
B.  Transition Period for Certain Biological Products ........................................................ 4 
III.  INTERPRETATION OF THE DEEMED TO BE A LICENSE PROVISION ...... 4 
A.  FDAs Interpretation of Section 7002(e) of the BPCI Act............................................. 4 
1. FDA Interprets section 7002(e)(4) to be Limited to Approved Applications ...................... 5 
2. Removal of Biological Products from the Orange Book on March 23, 2020 ..................... 8 
3. Exclusivity ........................................................................................................................... 9 
B.  Recommendations for Sponsors of Proposed Protein Products Intended for 
Submission in an Application Under Section 505 of the FD&C Act ................................. 10 
1. Stand-Alone New Drug Applications ........................................................................... 10 
2. 505(b)(2) Applications ...................................................................................................... 11 
APPENDIX .................................................................................................................................. 14  Contains Nonbinding Recommendations 
 
 
Interpretation of the Deemed to be a License Provision of the 
Biologics Price Competition and Innovation Act of 2009 
 
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 staff 
responsible for this guidance as listed on the title page.   
 
 
 
I.  INTRODUCTION 
 
This guidance describes FDAs interpretation of the provision of the Biologics Price Competition 
and Innovation Act of 2009 (BPCI Act) under which an application for a biological product 
approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 
U.S.C. 355) as of March 23, 2020, will be deemed to be a license for the biological product 
under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) on March 23, 
2020.  Specifically, this guidance describes FDAs interpretation of the deemed to be a license 
provision in section 7002(e) of the BPCI Act for biological products that are approved under 
section 505 of the FD&C Act as of March 23, 2020 (the transition date).  This guidance also 
provides recommendations to sponsors of proposed protein products intended for submission in 
an application that may not receive final approval under section 505 of the FD&C Act on or 
before March 23, 2020, to facilitate alignment of product development plans with FDAs 
interpretation of section 7002(e) of the BPCI Act. 
 
Although the majority of therapeutic biological products have been licensed under section 351 of 
the PHS Act, some protein products historically have been approved under section 505 of the 
FD&C Act (see the Appendix to this guidance for examples of such products).  On March 23, 
2010, the BPCI Act was enacted as part of the Patient Protection and Affordable Care Act 
(Public Law 111-148).  The BPCI Act clarified the statutory authority under which certain 
protein products will be regulated by amending the definition of a biological product2 in 
section 351(i) of the PHS Act to include a protein (except any chemically synthesized 
                                                 
1 This guidance has been 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.
 
2 As amended by the BPCI Act, a biological product is defined, in relevant part, as a virus, therapeutic serum, 
toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically 
synthesized polypeptide), or analogous product . . . applicable to the prevention, treatment, or cure of a disease or 
condition of human beings (see section 351(i) of the PHS Act, see also 21 CFR 600.3(h)). 
 
 
1  Contains Nonbinding Recommendations 
 
polypeptide),3 and describing procedures for submission of a marketing application for certain 
biological products.  
 
The BPCI Act requires that a marketing application for a biological product (that previously 
could have been submitted under section 505 of the FD&C Act) must be submitted under section 
351 of the PHS Act; this requirement is subject to certain exceptions during a 10-year transition 
period ending on March 23, 2020 (see section 7002(e)(1)-(3) and (e)(5) of the BPCI Act and 
section II of this guidance).  On March 23, 2020 (i.e., the transition date), an approved 
application for a biological product under section 505 of the FD&C Act shall be deemed to be a 
license for the biological product under section 351 of the PHS Act (see section 7002(e)(4) of the 
BPCI Act).  This guidance sets forth FDAs current interpretation of section 7002(e) of the BPCI 
Act. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
II.  BACKGROUND 
 
A.  BPCI Act 
 
The BPCI Act amended the PHS Act and other statutes to create an abbreviated licensure 
pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or 
interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 
7003 of the BPCI Act).  The objectives of the BPCI Act are conceptually similar to those of the 
Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(commonly referred to as the Hatch-Waxman Amendments), which established abbreviated 
pathways for the approval of drug products under section 505(b)(2) and 505(j) of the FD&C Act.  
An abbreviated licensure pathway for biological products can present challenges given the 
scientific and technical complexities that may be associated with the generally larger and 
typically more complex structure of biological products, as well as the processes by which such 
                                                 
3 FDA has described its interpretation of the statutory terms protein and chemically synthesized polypeptide in 
the amended definition of biological product in guidance.  See draft guidance for industry New and Revised Draft 
Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2).  When final, this guidance will 
represent FDAs current thinking on this topic.  FDAs guidances for industry are available on the FDA Drugs 
guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs web 
guidance page.  In addition, in the Federal Register of December 12, 2018, FDA also has issued a proposed rule to 
amend its regulation that defines biological product to incorporate changes made by the BPCI Act, and to provide 
its interpretation of the statutory terms protein and chemically synthesized polypeptide.  When final, this 
regulation will codify FDAs interpretation of these terms. 
 
 
 
  2  Contains Nonbinding Recommendations 
 
products are manufactured.  Most biological products are produced in a living system such as a 
microorganism, or plant or animal cells, whereas small molecule drugs are typically 
manufactured through chemical synthesis. 
 
Section 351(k) of the PHS Act, added by the BPCI Act, sets forth, among other things, the 
requirements for an application for a proposed biosimilar product and an application or a 
supplement for a proposed interchangeable product.  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 (section 351(i)(2) of the PHS Act).  A 351(k) application 
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, unless FDA determines, in its discretion, that certain studies are 
unnecessary in a 351(k) application (see section 351(k)(2) of the PHS Act).  To meet the 
standard for interchangeability, an applicant must provide sufficient information to 
demonstrate biosimilarity, 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 health care 
provider (see section 351(i)(3) of the PHS Act). 
 
The BPCI Act also includes, among other provisions:  
 
  A 12-year exclusivity period from the date of first licensure of certain reference products, 
during which approval of a 351(k) application referencing that product may not be made 
effective (see section 351(k)(7) of the PHS Act)  
 
  A 4-year exclusivity period from the date of first licensure of certain reference products, 
during which a 351(k) application referencing that product may not be submitted (see 
section 351(k)(7) of the PHS Act) 
 
  An exclusivity period for the first biological product determined to be interchangeable 
with the reference product for any condition of use, during which a second or subsequent 
biological product may not be determined interchangeable with that reference product 
(see section 351(k)(6) of the PHS Act) 
 
  Procedures for identifying and resolving patent disputes involving applications submitted 
under section 351(k) of the PHS Act (see section 351(l) of the PHS Act) 
 
  3  Contains Nonbinding Recommendations 
 
B.  Transition Period for Certain Biological Products 
 
Section 7002(e) of the BPCI Act provides that a marketing application for a biological product 
(that previously would have been submitted under section 505 of the FD&C Act) must be 
submitted under section 351 of the PHS Act, subject to the following exception during the 
transition period described below: 
 
  An application for a biological product may be submitted under section 505 of the FD&C 
Act not later than March 23, 2020, if the biological product is in a product class4 for 
which a biological product in such product class was approved under section 505 of the 
FD&C Act not later than March 23, 2010. 
 
  However, an application for a biological product may not be submitted under section 
505 of the FD&C Act if there is another biological product approved under section 
351(a) of the PHS Act that could be a reference product5 if such application were 
submitted under section 351(k) of the PHS Act. 
 
An approved application for a biological product under section 505 of the FD&C Act shall be 
deemed to be a license for the biological product under section 351 of the PHS Act (a deemed 
Biologics License Application (BLA)) on March 23, 2020. 
 
III.  INTERPRETATION OF THE DEEMED TO BE A LICENSE PROVISION 
 
A.  FDAs Interpretation of Section 7002(e) of the BPCI Act 
 
Section 7002(e) of the BPCI Act is directed primarily to the submission of an application for a 
biological product during the transition period ending on March 23, 2020.6  Though the transition 
scheme described in section 7002(e) of the BPCI Act culminates with the deemed to be a 
license provision in section 7002(e)(4), the statute is silent regarding the process for 
                                                 
4 FDA has interpreted the statutory term product class 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 (see guidance 
for industry Questions and Answers on Biosimilar Development and the BPCI Act, at Q&A II.2).
 
5 The term reference product means the single biological product licensed under section 351(a) of the PHS Act 
against which a biological product is evaluated in an application submitted under section 351(k) (see section 
351(i)(4) of the PHS Act).
 
6 General references in this guidance to applications submitted or approved under section 505 of the FD&C Act 
also may include abbreviated new drug applications (ANDAs), to the extent applicable.  An ANDA generally must 
contain information to demonstrate, among other things, that the proposed generic drug has the same active 
ingredient(s), conditions of use, dosage form, route of administration, strength, and (with certain permissible 
differences) labeling as the reference listed drug (section 505(j)(2)(A) of the FD&C Act).  Given the complexity of 
protein molecules and limitations of current analytical methods, it may be difficult for manufacturers of proposed 
protein products to demonstrate that the active ingredient in their proposed product is the same as the active 
ingredient in an already approved product, and thus ANDAs are not a focus of this guidance.  There are no currently 
marketed biological products that were approved through the ANDA pathway. 
 
 
  4  Contains Nonbinding Recommendations 
 
accomplishing the transition of approved new drug applications (NDAs) to deemed BLAs, or the 
implications of the deeming process on pending applications.7   
1.  FDA Interprets section 7002(e)(4) to be Limited to Approved Applications 
 
Section 7002(e)(4) of the BPCI Act provides: 
 
An approved application for a biological product under section 505 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355) shall be deemed to be a license for the 
biological product under such section 351 [of the PHS Act] on the date that is 10 years 
after the date of enactment of [the BPCI Act]. 
 
Section 7002(e)(4) is explicitly limited to an approved application under section 505 of the 
FD&C Act.  Moreover, while this provision explicitly provides that an approved application 
under section 505 of the FD&C Act shall be deemed to be a BLA on the transition date, the 
statute does not provide a means for deeming an approved NDA to be an approved BLA prior to, 
or after, the transition date.8  Finally, section 7002(e) of the BPCI Act does not provide a basis 
for the Agency to treat approved NDAs for biological products as both NDAs and BLAs after 
such applications are deemed to be BLAs.  Therefore, FDA interprets section 7002(e) of the 
BPCI Act to plainly mean that, on March 23, 2020, only approved NDAs will be deemed to be 
BLAs.  After March 23, 2020, the Agency will not approve any application submitted under 
section 505 of the FD&C Act for a biological product subject to the transition provision that is 
pending or tentatively approved.9,10  As a corollary, applications for biological products approved 
                                                 
7 In other legislation, Congress has described the implications of transitioning applications for drug products from 
one statutory scheme to another, while also describing the process that would be used in effecting the transition.  
See, e.g., section 107(c) of the Drug Amendments of 1962 (Pub. L. 87-781) (providing that all NDAs effective on 
the day immediately preceding the date of enactment of the Drug Amendments of 1962 shall be deemed approved as 
of the enactment date, and that the provision for withdrawal of approval of an application for lack of effectiveness 
generally would not apply to such deemed NDAs for a period of 2 years after the enactment date); section 125 of the 
Food and Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105-115) (repealing section 507 of 
the FD&C Act and providing that an application for an antibiotic drug approved under section 507 of the FD&C Act 
on the day before enactment of FDAMA shall, on and after the date of enactment, be considered to be an NDA 
submitted and filed under section 505(b) and approved under section 505(c) or an ANDA filed and approved under 
505(j)).
 
8 Compare section 7002(e)(4) of the BPCI Act with section 125 of FDAMA (providing that an approved application 
for the marketing of an antibiotic drug under section 507 of the FD&C Act shall, on and after such date of 
enactment, be considered to be an application that was submitted and filed under section 505(b) . . .  and approved 
for safety and effectiveness under section 505(c) (emphasis added)) and FDAs guidance for industry Repeal of 
Section 507 of the Federal Food, Drug, and Cosmetic Act (All action letters must use the 505(b) or 505(j) 
templates, even for drugs that originally were submitted under section 507, but are the subject of Agency action on 
or after November 21, 1997.).
 
9 Tentative approval means that an NDA or ANDA otherwise meets the requirements for approval under the FD&C 
Act but cannot be approved until the expiration of an applicable period of patent and/or exclusivity protection.  A 
drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an 
approval letter after any necessary additional review of the NDA or ANDA (see 21 CFR 314.105; see also 21 CFR 
314.107).
 
10 The fact that section 7002(e)(2) of the BPCI Act permits submission of an application under section 505 of the 
FD&C Act not later than the transition date does not change this conclusion.  Section 7002(e)(2) is not 
 
  5  Contains Nonbinding Recommendations 
 
under section 505 of the FD&C Act will no longer exist as NDAs and will be replaced by 
approved BLAs under section 351 of the PHS Act.11 
 
Accordingly, an original 505(b)(2) application (including a resubmission) for a biological 
product that relies, at least in part, on FDAs finding of safety and/or effectiveness for a listed 
drug that is a biological product will receive a complete response if the application is pending at 
the end of the day (11:59 pm Eastern Daylight Time (EDT)) on Friday, March 20, 2020, because 
the NDA for the listed drug relied upon will no longer exist at midnight on Monday, March 23, 
2020.  An original application (including a resubmission) for a biological product that has been 
submitted as a 505(b)(1) application (i.e., a stand-alone NDA) or a 505(b)(2) application that 
does not rely, to any extent, on FDAs finding of safety and/or effectiveness for a listed drug that 
is a biological product (e.g., a 505(b)(2) application that relies on non-product-specific published 
literature) and is pending at the end of the day (11:59 pm EDT) on March 23, 2020, will receive 
a complete response.12  Such applications may, for example, be withdrawn and submitted under 
section 351(a) or 351(k) of the PHS Act, as appropriate.  We provide an overview of key 
dates/times below and recommendations to minimize the impact on development programs for 
any proposed biological products intended for submission under section 505 of the FD&C Act 
that may not be able to receive final approval by March 23, 2020. 
 
                                                 
inconsistent with the interpretation set forth here because, among other things, Congress presumably is aware that 
approval decisions can take a variable amount of time, and thus did not settle on a date by which such submissions 
would no longer be permitted.  Moreover, if Congress meant to allow for pending applications submitted under 
section 505 of the FD&C Act to be deemed BLAs after the transition, it knew how to do so explicitly.  See section 
125 of FDAMA, supra note 8.
 
11 See FDAs draft guidance for industry The Deemed to be a License Provision of the BPCI Act:  Questions and 
Answers (Transition Q&A Draft Guidance) for additional information, including whether an approved application 
for a biological product under section 505 of the FD&C Act will be deemed a license for the biological product 
under section 351(a) or 351(k) of the PHS Act and administrative issues associated with the transition (including 
BLA numbers and user fee questions).  When final, that guidance will represent FDAs current thinking on this 
topic.
 
12 An applicant who seeks to obtain final approval of a tentatively approved NDA for a biological product on or 
before March 23, 2020, would need to submit an amendment requesting final approval.  FDA recommends that the 
amendment should be submitted by a date that allows adequate time for FDA review and approval before March 23, 
2020.  Please refer to the recommended timeframes provided in the tentative approval letter and any applicable 
guidance for further information and contact the relevant review division with any questions (including questions 
about whether an inspection may be needed).  An amendment requesting final approval of a tentatively approved 
application should provide the legal/regulatory basis for the request for final approval and should include a copy of 
any relevant court action, written consent to approval by the patent owner or exclusive patent licensee, or waiver of 
exclusivity by the relevant NDA holder, as appropriate, that has not been submitted previously to FDA under 21 
CFR 314.107(e).  In addition to a safety update, the amendment should identify whether there are any changes in the 
conditions under which the product was tentatively approved, i.e., updated labeling; chemistry, manufacturing, and 
controls data; and, as applicable, Risk Evaluation and Mitigation Strategy (REMS).  Any changes require FDA 
review before final approval and the goal date for FDA review will be set accordingly.
 
  6  Contains Nonbinding Recommendations 
 
Table:  Overview of Key Dates/Times Related to the Statutory Transition Provision 
Date/Time  Relevant Application Type  Event 
Friday, March 20, 2020,  Pending 505(b)(2) applications  Deadline for any pending 505(b)(2) 
11:59 pm (EDT)  that rely, at least in part, on FDAs  application of this type to be approved 
finding of safety and/or  under the FD&C Act. 
effectiveness for a listed drug that 
is a biological product 
Monday, March 23, 2020,  Approved NDAs for biological  Approved NDAs for biological 
12:00 am (EDT)  products  products are deemed to be BLAs, and 
cease to exist as NDAs. 
Monday, March 23, 2020,  351(k) BLA that relies on a  A 351(k) BLA can be submitted for a 
12:01 am (EDT)  deemed BLA for its reference  proposed biosimilar or a proposed 
product  interchangeable to a biological 
reference product that is the subject of 
a deemed BLA. 
Monday, March 23, 2020,  Approved NDAs for biological  FDA intends to send a letter to each 
during hours in which  products  holder of an approved NDA for a 
FDA is open for business  biological product that advises that the 
approved NDA has been deemed to be 
a BLA by operation of the statute, and 
no longer exists as an NDA.  FDA 
intends to update the Orange Book to 
remove biological product listings. 
Monday, March 23, 2020,  Pending 505(b)(1) applications and  Deadline for any pending 505(b)(1) 
11:59 pm (EDT)   pending 505(b)(2) applications that  application or any pending 505(b)(2) 
do not rely, to any extent, on  application of this type to be approved 
FDAs finding of safety and/or  under the FD&C Act.  An NDA 
effectiveness for a listed drug that  approved on March 23, 2020, will be 
is a biological product  deemed to be a BLA immediately after 
approval under the FD&C Act. 
 
FDA intends to assist applicants who may be affected by section 7002(e) of the BPCI Act, where 
feasible and appropriate.  For example, during the review of a BLA submitted after the transition 
date under section 351(a) or 351(k) of the PHS Act for a proposed biological product that was 
previously submitted, but not approved, in an application under section 505 of the FD&C Act, 
FDA intends to consider any previously conducted scientific review by the Agency of such 
previous application under the FD&C Act, to the extent that such review is relevant to, and 
consistent with, applicable requirements of section 351 of the PHS Act. 
 
An application generally includes all amendments and supplements to the application.13  We 
recognize that there may be one or more supplements submitted to an approved NDA for a 
biological product before March 23, 2020, that is pending on March 23, 2020.  Such supplements 
may include a prior approval supplement (e.g., an efficacy supplement,14 a labeling supplement, 
                                                 
13 See 21 CFR 314.3(b) (definition of application).   
14 An efficacy supplement is a supplement to an approved NDA proposing to make one or more related changes 
from among the following changes to product labeling: (1) Add or modify an indication or claim; (2) Revise the 
dose or dose regimen; (3) Provide for a new route of administration; (4) Make a comparative efficacy claim naming 
 
  7  Contains Nonbinding Recommendations 
 
or a manufacturing supplement), a supplement for changes being effected (CBE) in 30 days (for 
certain chemistry, manufacturing, and controls changes), or a supplement for changes being 
effected upon receipt by the Agency of the supplement (for certain safety-related labeling 
changes or any other labeling change that FDA specifically requests to be submitted in a CBE 
supplement).15  At the time that FDA deems the approved NDA for a biological product to be a 
BLA on the transition date, FDA intends to also administratively convert any pending 
supplement to such approved NDA to a pending supplement to the deemed BLA, and to review 
such supplements under applicable standards for BLAs.  For example, a pending stand-alone 
efficacy supplement to a stand-alone NDA16 (e.g., a supplement intended to address a post-
approval requirement or post-approval commitment) will be administratively converted to a 
pending efficacy supplement to the corresponding deemed 351(a) BLA on the transition date and 
reviewed under applicable standards for 351(a) BLAs.  Similarly, a pending CBE supplement to 
an application submitted under the FD&C Act will be administratively converted to a pending 
CBE supplement to the deemed BLA on the transition date, irrespective of whether the change 
described in the CBE supplement has been implemented before or after the transition date.  The 
Agency also intends to maintain the same goal date, where applicable, for completion of its 
review of such supplements. 
2.  Removal of Biological Products from the Orange Book on March 23, 2020 
 
FDA intends to remove biological products that have been approved in NDAs from FDAs 
Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book)17 on 
March 23, 2020, based on the Agencys position that these products are no longer listed drugs 
and such NDAs may not be relied upon by a 505(b)(2) applicant (or ANDA applicant) for 
approval. After March 23, 2020, FDA will not approve any NDA (or ANDA), including those 
  
that are pending or tentatively approved, for a biological product. 
 
Moreover, with the exception of orphan drug exclusivity and pediatric exclusivity, the 
exclusivity provisions of the FD&C Act serve to limit the submission or approval of applications 
under section 505 of the FD&C Act, but not under section 351 of the PHS Act.  Section 7002(e) 
of the BPCI Act provides that no applications for biological products may be submitted under 
section 505 of the FD&C Act after the transition date.  Accordingly, on March 23, 2020, any 
unexpired period of exclusivity associated with an approved NDA for a biological product 
subject to section 7002(e) of the BPCI Act (e.g., 5-year exclusivity or 3-year exclusivity) would 
                                                 
another drug product; (5) Significantly alter the intended patient population; (6) Change the marketing status from 
prescription to over-the-counter use; (7) Provide for, or provide evidence of effectiveness necessary for, the 
traditional approval of a product originally approved under subpart H of part 314; or (8) Incorporate other 
information based on at least one adequate and well-controlled clinical study (21 CFR 314.3(b)). 
15 See generally 21 CFR 314.70. 
16 See section III.B.1 of this guidance for information on stand-alone NDAs.  There may be additional 
considerations for a pending 505(b)(2) efficacy supplement to a stand-alone NDA and a pending 505(b)(2) efficacy 
supplement to a 505(b)(2) application. 
17 Biological products approved in NDAs that are deemed to be BLAs will be listed in FDAs Lists of Licensed 
Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations (the 
Purple Book) on or shortly after the March 23, 2020, transition date. 
  8  Contains Nonbinding Recommendations 
 
cease to have any effect, and any patents listed in the Orange Book would no longer be relevant 
for purposes of determining the timing of approval of a 505(b)(2) application (or ANDA).  
However, any unexpired period of orphan drug exclusivity would continue to apply to the 
biological product for the protected use after the transition date, because orphan drug exclusivity 
can block the approval of a drug approved under section 505 of the FD&C Act or a biological 
product licensed under section 351 of the PHS Act (see section 527 of the FD&C Act (21 U.S.C. 
360cc)).  Similarly, any unexpired period of pediatric exclusivity associated with an approved 
NDA for a biological product would continue to apply to a deemed 351(a) BLA on and after 
March 23, 2020, provided that the conditions in section 351(m) of the PHS Act are met.  Any 
post-approval requirements or post-approval commitments, including any pediatric assessments 
necessary to comply with the Pediatric Research Equity Act (PREA) (Public Law 108-155), also 
would transfer to the deemed BLA. 
3.  Exclusivity 
 
FDA interprets section 7002(e) of the BPCI Act and section 351 of the PHS Act to mean that an 
approved NDA for a biological product that will be deemed to be licensed under section 351(a) 
of the PHS Act on March 23, 2020, can be a reference product for a proposed biosimilar product 
or a proposed interchangeable product (see section 351(i)(4) of the PHS Act).  However, a 
biological product that was first approved in an NDA under section 505 of the FD&C Act and 
deemed licensed under section 351(a) of the PHS Act on March 23, 2020, will not have been 
first licensed under subsection (a) for purposes of section 351(k)(7) of the PHS Act.  Thus, 
such a biological product will not be eligible for exclusivity under section 351(k)(7)(A) and (B) 
of the PHS Act.   
 
Section 351(k)(7)(A) and (B) of the PHS Act describe a 12-year exclusivity period during which 
FDA may not approve a 351(k) application and a 4-year exclusivity period during which an 
applicant may not submit a 351(k) application (reference product exclusivity).  Except as 
provided in section 351(k)(7)(C) of the PHS Act, these periods begin on the date on which the 
reference product was first licensed under subsection (a) [referring to section 351(a) of the PHS 
Act].  However, section 351(k)(7)(C) of the PHS Act provides that reference product 
exclusivity shall not apply to a license for or approval of: 
 
  A supplement for the biological product that is the reference product; or 
 
  A subsequent application filed by the same sponsor or manufacturer of the biological 
product that is the reference product (or a licensor, predecessor in interest, or other 
related entity) under the conditions set forth in section 351(k)(7)(C) of the PHS Act.18  
 
Nothing in the Biologics Price Competition and Innovation Act suggests that Congress intended 
for biological products approved under section 505 of the FD&C Act  some of which were 
approved decades ago  to obtain a 12-year period of reference product exclusivity upon being 
                                                 
18 See section 351(k)(7)(C) of the PHS Act and FDAs guidance for industry Reference Product Exclusivity for 
Biological Products Filed Under Section 351(a) of the PHS Act.  When final, this guidance will represent FDAs 
current thinking on this topic. 
  9  Contains Nonbinding Recommendations 
 
deemed to be licensed under section 351(a) of the PHS Act.  Reference product exclusivity 
recognizes the fact that the sponsor of an eligible reference product generated (and submitted for 
review) the data and information required to obtain a license under section 351(a) of the PHS Act 
and limits competition from biosimilar and interchangeable products for a limited period of time.  
The biological products that will be deemed to have BLAs on the transition date, however, have 
already obtained marketing approval under a different statutory authority.  Allowing such 
products to obtain a separate 12-year period of reference product exclusivity would 
inappropriately impede biosimilar or interchangeable product competition in several product 
classes.   
 
Recognizing these principles, FDA interprets section 7002(e) of the BPCI Act together with 
section 351(k)(7) of the PHS Act such that section 351(k)(7)(A)-(B) of the PHS Act applies only 
to products that have undergone review and licensing under section 351(a), and not to biological 
products that will be deemed licensed under section 351(a) of the PHS Act on the transition date.
  
At the same time, FDA interprets the limitations on eligibility for reference product exclusivity 
in section 351(k)(7)(C) of the PHS Act to apply to any reference product, without regard to 
whether such product was first licensed under subsection (a) or instead deemed to be a license 
under section 7002(e) of the BPCI Act.  Nothing in the BPCI Act suggests that Congress 
intended holders of deemed BLAs to be able to circumvent the statutory limitations on eligibility 
for a 12-year period of reference product exclusivity through subsequent submissions simply 
because the previous reference product was deemed to be licensed under section 7002(e).  
Therefore, FDA interprets section 351(k)(7) of the PHS Act together with section 7002(e) of the 
BPCI Act such that section 351(k)(7)(C) will operate to bar supplements to deemed BLAs and, 
where applicable, subsequent BLAs from being eligible for their own periods of reference 
product exclusivity.   
 
B.  Recommendations for Sponsors of Proposed Protein Products Intended for 
Submission in an Application Under Section 505 of the FD&C Act 
 
Sponsors of development programs for proposed protein products should evaluate whether a 
planned submission under section 505 of the FD&C Act would allow adequate time for approval 
of the application prior to March 23, 2020, considering, among other things, whether the 
submission may require a second cycle of review and, for certain types of applications, whether 
unexpired patents or exclusivity may delay final approval.  FDAs recommendations for 
sponsors are based on whether a stand-alone or abbreviated development program is planned.  
 
1.  Stand-Alone New Drug Applications 
 
An application submitted under section 505(b)(1) of the FD&C Act (i.e., a stand-alone NDA) 
contains full reports of investigations of safety and effectiveness that were conducted by or for 
the applicant or for which the applicant has a right of reference or use.  Sponsors of a proposed 
protein product intended for submission in an NDA under section 505(b)(1) of the FD&C Act 
should consider submitting a BLA under section 351(a) of the PHS Act.  A 351(a) BLA for a 
biological product can be submitted before, on, or after March 23, 2020.  Sponsors can contact 
  10  Contains Nonbinding Recommendations 
 
the relevant review division within the Office of New Drugs in FDAs CDER with any questions 
about a BLA submission.19 
2.  505(b)(2) Applications 
 
A 505(b)(2) application is an NDA that contains full reports of investigations of safety and 
effectiveness, where at least some of the information required for approval comes from studies 
not conducted by or for the applicant and for which the applicant has not obtained a right of 
reference or use (e.g., FDAs finding of safety and/or effectiveness for a listed drug or published 
literature).  A 505(b)(2) application that seeks to rely on a listed drug must contain adequate data 
and information to demonstrate that the proposed product is sufficiently similar to the listed drug 
to justify reliance, in part, on FDAs finding of safety and/or effectiveness for the listed drug.  
Any aspects of the proposed product that differ from the listed drug must be supported by 
adequate data and information to support the safety and effectiveness of the proposed product. 
 
Congress did not provide an approval pathway under the PHS Act that directly corresponds to 
section 505(b)(2) of the FD&C Act.  Accordingly, there are additional considerations for 
sponsors of proposed protein products intended for submission in a 505(b)(2) application or a 
505(b)(2) efficacy supplement, and sponsors may contact the relevant review division with any 
questions.  If a sponsor anticipates that a planned 505(b)(2) application or 505(b)(2) efficacy 
supplement may not receive final approval before the transition date (e.g., due to the need for a 
second cycle of review, applicable unexpired exclusivity or listed patents, or a stay of approval 
due to patent infringement litigation), the sponsor should consider the following options: 
 
  Modifying the development program to support submission of an application or efficacy 
supplement under section 351(a) of the PHS Act (i.e., a stand-alone BLA) before or 
after March 23, 2020.  This may involve, for example, obtaining a right of reference from 
the application holder for the listed drug on which the proposed 505(b)(2) application or 
505(b)(2) efficacy supplement would have relied or conducting studies with the proposed 
product to provide the scientific data that otherwise would have been relied upon to 
support approval of the application or the change proposed in the supplement, as 
applicable.20  
 
  Modifying the development program to support submission of a 351(k) BLA for a 
proposed biosimilar product or a proposed interchangeable product at such time as there 
is a biological product licensed under section 351(a) of the PHS Act that could be a 
reference product.   
 
                                                 
19 FDA has taken measures to minimize differences in the review and approval of products required to have 
approved BLAs under section 351 of the PHS Act and products required to have approved NDAs under section 
505(b)(1) of the FD&C Act (see section 123(f) of FDAMA).  However, certain differences continue to exist.  For 
additional information on how FDA intends to address these issues, see the Transition Q&A Draft Guidance or 
contact the relevant review division.  When final, this guidance will represent FDAs current thinking on this topic.
 
20 FDA has issued guidance for industry on Exocrine Pancreatic Insufficiency Drug Products  Submitting NDAs 
and is considering how the concepts described in the guidance would apply to proposed pancreatic enzyme products 
submitted under the PHS Act.
 
  11  Contains Nonbinding Recommendations 
 
Sponsors evaluating whether a proposed product could be submitted under section 351(k) of the 
PHS Act should consider whether they would be able to provide information demonstrating that, 
among other things, the proposed product: 
 
  Is highly similar to a single reference product licensed under section 351(a) of the PHS 
Act, and that there are no clinically meaningful differences between the proposed 
product and the reference product in terms of safety, purity, and potency; 
 
  Has the same route of administration, dosage form, and strength as the reference product; 
  
  Utilizes the same mechanism(s) of action as the reference product for the proposed 
condition(s) of use (but only to the extent that the mechanism(s) of action are known); 
and 
 
  Seeks licensure for a condition(s) of use (e.g., indication, dosing regimen) previously 
approved for the reference product.21 
 
A sponsor of a proposed biological product that could meet the requirements for a proposed 
biosimilar and other applicable requirements would be able to submit a 351(k) BLA that cites the 
listed drug as its reference product after the NDA for the listed drug is deemed to be a BLA (or 
after another product that could be a reference product for the proposed product is licensed under 
section 351(a) of the PHS Act).  Sponsors that intend to adapt their development programs to 
meet the requirements for a submission under section 351(k) of the PHS Act can request 
meetings with FDA, including a Biosimilar Biological Product Development (BPD) Type 3 
meeting, before March 23, 2020, to support the development and review of a proposed biosimilar 
product or a proposed interchangeable product.  Such meetings may be based on relevant 
comparative data with a listed drug that is the intended reference product (i.e., the listed drug 
that is intended to be the reference product after the NDA for such drug is deemed to be licensed 
under section 351(a) of the PHS Act).   
 
Proposed products that are intended to differ in certain respects (e.g., different dosage forms, 
routes of administration, strengths, or conditions of use) from a previously approved product 
likely would need to be submitted under section 351(a) of the PHS Act and meet applicable 
statutory and regulatory requirements for a 351(a) BLA.  Such products likely would be unable 
to use the 351(k) pathway to abbreviate their development program due to lack of a reference 
product or the inability to meet the statutory requirements for a proposed biosimilar product. 
 
A sponsor may contact the relevant review division within the Office of New Drugs in FDAs 
CDER to request advice on a product-specific basis regarding the development of a protein 
product intended for submission in an application under the FD&C Act (during the transition 
                                                 
21 See section 351(k) of the PHS Act; see also, generally, FDAs guidance documents on biosimilar products.
 
 
  12  Contains Nonbinding Recommendations 
 
period described in section 7002(e) of the BPCI Act) or under section 351(a) or 351(k) of the 
PHS Act, as appropriate.22 
 
                                                 
22 For information on requesting a formal meeting regarding the development of a proposed biosimilar product 
intended for submission under section 351(k) of the PHS Act, see FDAs draft guidance for industry Formal 
Meetings Between the FDA and Sponsors or Applicants of BsUFA Products.  For information on requesting a formal 
meeting regarding the development of a biological product intended for submission in an NDA before March 23, 
2020, or in a 351(a) BLA, see FDAs draft guidance for industry Formal Meetings Between the FDA and Sponsors 
or Applicants of PDUFA Products.  When final, these guidances will represent FDAs current thinking on these 
topics. 
  13  Contains Nonbinding Recommendations 
 
APPENDIX 
 
Examples of Biological Products That Have Been Approved Under the FD&C Act 
 
 
chorionic gonadotropin products 
desirudin products 
follitropin products, urofollitropin products, and menotropins products 
hyaluronidase products 
imiglucerase products 
insulin products, insulin mix products, and insulin analog products  
(e.g., insulin aspart, insulin detemir, insulin glargine, insulin glulisine, and insulin 
lispro products) 
mecasermin products 
pancrelipase products 
pegademase products 
pegvisomant products 
sacrosidase products 
somatropin products 
taliglucerase alfa products and velaglucerase alfa products 
thyrotropin alfa products 
 
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