Biosimilarity and Interchangeability:  
Additional Draft Q&As on Biosimilar 
Development and the BPCI Act  
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted as electronic 
comments to https://www.regulations.gov.  Submit written comments to the Dockets 
Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD  20852.  All comments should be identified with the docket number FDA-2011-
D-0611. 
 
For questions regarding this draft document, contact (CDER) Sandra Benton 301-796-1042, or 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.  
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2023 
Biosimilars 
 
Revision 1 
   
Biosimilarity and Interchangeability:  
Additional Draft Q&As on Biosimilar 
Development and the BPCI Act   
 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
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and/or 
Office of Communication, Outreach and Development  
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 Food and Drug Administration 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances  
 
 
 
 
   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2023 
Biosimilars 
 
Revision 1 
 
  Contains Nonbinding Recommendations 
DraftNot for Implementation 
TABLE OF CONTENTS 
 
 
 
INTRODUCTION......................................................................................................................... 1 
BACKGROUND ........................................................................................................................... 3 
QUESTIONS AND ANSWERS ................................................................................................... 4 
I.  BIOSIMILARITY OR INTERCHANGEABILITY ................................................................... 4 
Q.I.25  How may the applicant seek FDA review for licensure for an interchangeable biosimilar, 
and how does FDA intend to review an application submitted under section 351(k) that seeks 
licensure as an interchangeable biosimilar and includes data and information sufficient to 
support licensure of the product as a biosimilar product, but does not contain data and 
information sufficient to support licensure of the product as an interchangeable biosimilar? ....... 4 
Q.I.26   How should a 351(a) BLA holder proceed if it seeks licensure of its biological product 
under section 351(k) as biosimilar to or interchangeable with another biological product licensed 
under section 351(a) (a reference product)? ............................................................................... 6 
II.  PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA FOR A 
BIOLOGICAL PRODUCT ....................................................................................................... 7 
III. EXCLUSIVITY .............................................................................................................................. 8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Biosimilarity and Interchangeability:  Additional Draft Q&As on 
2  Biosimilar Development and the BPCI Act  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  INTRODUCTION 
15   
16  This draft guidance provides answers to common questions from prospective applicants and 
17  other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 
18  (BPCI Act).  The question and answer (Q&A) format is intended to inform prospective 
19  applicants and facilitate the development of proposed biosimilar products and proposed 
20  interchangeable products,2 as well as describe FDAs interpretation of certain statutory 
21  requirements added by the BPCI Act. 
22   
23  The BPCI Act created an abbreviated licensure pathway in section 351(k) of the Public Health 
24  Service Act (PHS Act) (42 U.S.C. 262(k)) for biological products shown to be biosimilar to, or 
25  interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 
26  7003 of the Patient Protection and Affordable Care Act (Public Law 111148) (ACA)).  FDA 
27  believes that guidance for industry that provides answers to commonly asked questions regarding 
28  FDAs interpretation of the BPCI Act will enhance transparency and facilitate the development 
29  and approval of biosimilar and interchangeable products.  In addition, these Q&As respond to 
30  questions the Agency has received from prospective applicants regarding the submission of 
31  biologics license applications (BLAs) for biosimilar and interchangeable products.  FDA may 
32  provide additional Q&As through draft guidances as appropriate. 
 
1 This draft 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 (FDA or the Agency).  You may 
submit comments on a guidance at any time.  Submit comments on this guidance to Docket No. FDA-2011-D-0611 
(available at https://www.regulations.gov/docket/FDA-2011-D-0611).  See the instructions in that docket for 
submitting comments on this guidance. 
 
2 In this draft guidance, the following terms are used to describe biological products licensed under section 351(k) of 
the PHS Act:  (1) biosimilar or biosimilar product refers to a product that FDA has determined to be biosimilar to 
the reference product (see sections 351(i)(2) and 351(k)(2) of the PHS Act) and (2) interchangeable biosimilar or 
interchangeable product refers to a biosimilar product that FDA has also determined to be interchangeable with the 
reference product (see sections 351(i)(3) and 351(k)(4) of the PHS Act).  The terms proposed biosimilar product 
and proposed interchangeable product are used to describe a product that is under development or is the subject of a 
pending 351(k) BLA.  Biosimilarity, interchangeability, and related issues are discussed in more detail in the 
BACKGROUND section of this draft guidance. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
33   
34  This draft guidance revises the draft guidance for industry Biosimilarity and Interchangeability:  
35  Additional Draft Q&As on Biosimilar Development and the BPCI Act (November 2020) by 
36  withdrawing Q.I.27 and Q.I.28 and retaining Q.I.25 and Q.I.26.  This draft guidance does not 
37  include new Q&As or make changes to currently issued draft Q&As.  Additional information 
38  about the Q&A format for this draft guidance is provided in the Background section. 
39   
40  After FDA has considered any comments on a draft Q&A, the Q&As in this guidance will be 
41  finalized by adding the Q&A, as a revision, to the final guidance for industry Questions and 
42  Answers on Biosimilar Development and the BPCI Act (Revision 2) (September 2021),3 as 
43  appropriate.  The final guidance is part of a series of guidances that FDA developed to facilitate 
44  development of biosimilar and interchangeable products. 
45   
46  The final guidances issued to date address a broad range of issues, including: 
47   
48    Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference 
49  Product (December 2016) 
50   
51    Considerations in Demonstrating Interchangeability With a Reference Product (May 
52  2019) 
53   
54    Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2) 
55  (September 2021) 
56   
57    Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 
58  2015) 
59   
60  In addition, FDA has published draft guidances related to the BPCI Act; when finalized, these 
61  guidances will represent the FDAs current thinking.  These draft guidances include: 
62   
63    Development of Therapeutic Protein Biosimilars:  Comparative Analytical Assessment 
64  and Other Quality-Related Considerations (May 2019) 
65   
66    Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products 
67  (August 2023) 
68   
69    Labeling for Biosimilar and Interchangeable Biosimilar Products (September 2023) 
70   
71    New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3) 
72  (September 2021) 
73   
74    Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the 
75  PHS Act (August 2014) 
 
3 We update guidances periodically.  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. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76   
77  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
78  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
79  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
80  the word should in Agency guidances means that something is suggested or recommended, but 
81  not required.  
82   
83   
84  BACKGROUND 
85   
86  The BPCI Act 
87   
88  The BPCI Act was enacted as part of the ACA on March 23, 2010.  The BPCI Act amended the 
89  PHS Act and other statutes to create an abbreviated licensure pathway for biological products 
90  shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product 
91  (see sections 7001 through 7003 of the ACA).  Section 351(k) of the PHS Act, added by the 
92  BPCI Act, sets forth the requirements for the licensure of a proposed biosimilar or proposed 
93  interchangeable product. 
94   
95  Section 351(i) of the PHS Act defines biosimilarity to mean that the biological product is highly 
96  similar to the reference product notwithstanding minor differences in clinically inactive 
97  components and that there are no clinically meaningful differences between the biological 
98  product and the reference product in terms of the safety, purity, and potency of the product (see 
99  section 351(i)(2) of the PHS Act). 
100   
101  A BLA submitted under section 351(k) (a 351(k) BLA) of the PHS Act must contain, among 
102  other things, information demonstrating that the biological product is biosimilar to a reference 
103  product based upon data derived from analytical studies, animal studies, and a clinical study or 
104  studies (see section 351(k)(2)(A)(i)(I) of the PHS Act), unless FDA has determined that an 
105  element described in section 351(k)(2)(A)(i)(I) is unnecessary (see section 351(k)(2)(A)(ii) of 
106  the PHS Act).  To meet the standard for interchangeability, an applicant must provide 
107  sufficient information to demonstrate biosimilarity to the reference product and also to 
108  demonstrate that the biological product can be expected to produce the same clinical result as the 
109  reference product in any given patient, and if the biological product is administered more than 
110  once to an individual, the risk in terms of safety or diminished efficacy of alternating or 
111  switching between the use of the biological product and the reference product is not greater than 
112  the risk of using the reference product without such alternation or switch (see section 351(k)(4) 
113  of the PHS Act).  Interchangeable products may be substituted for the reference product without 
114  the intervention of the prescribing health care provider (see section 351(i)(3) of the PHS Act). 
115   
116  Question-and-Answer Guidance Format 
117   
118  FDA has been using the Q&A guidance format to describe the Agencys thinking on and update 
119  certain information and recommendations relevant to the development of biosimilar and 
120  interchangeable products.  This draft guidance includes only Q&As that are in draft form.  The 
121  guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
122  contains all Q&As that are final.  As FDA issues individual Q&As, they will first be 
123  incorporated into a Q&A draft guidance.  After FDA has considered any comments on draft 
124  Q&As received during the relevant comment period and, as appropriate, incorporated suggested 
125  changes to the Q&A, individual Q&As will be finalized and moved to the final guidance.   
126   
127  A Q&A that was previously in the final guidance may be withdrawn and moved to a draft 
128  guidance if FDA determines that the Q&A should be revised in some respect and reissued in a 
129  revised draft Q&A for comment.  A Q&A also may be withdrawn and removed from the Q&A 
130  guidance if, for instance, the issue addressed in the Q&A is addressed in another FDA guidance.   
131   
132  FDA will provide the publication date of the current version of each Q&A and information about 
133  whether the Q&A has been added to or modified in the relevant draft guidance.  FDA has 
134  maintained the original numbering of the Q&As used in the September 2021 final guidance for 
135  industry Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2), the 
136  September 2021 draft guidance for industry New and Revised Draft Q&As on Biosimilar 
137  Development and the BPCI Act (Revision 3), and the November 2020 draft guidance for industry 
138  Biosimilarity and Interchangeability:  Additional Draft Q&As on Biosimilar Development and 
139  the BPCI Act.  For ease of reference, a Q&A retains the same number when it moves from a draft 
140  guidance to the final guidance and, where appropriate, when a Q&A is withdrawn from the final 
141  guidance and moved to a draft guidance. 
142   
143   
144  QUESTIONS AND ANSWERS 
145   
146  I.  BIOSIMILARITY OR INTERCHANGEABILITY 
147   
148   
149  Q.I.25 How may the applicant seek FDA review for licensure for an interchangeable 
150  biosimilar, and how does FDA intend to review an application submitted under 
151  section 351(k) that seeks licensure as an interchangeable biosimilar and includes 
152  data and information sufficient to support licensure of the product as a biosimilar 
153  product, but does not contain data and information sufficient to support licensure 
154  of the product as an interchangeable biosimilar?   
155  [Draft November 2020] 
156   
157  A.I.25 To support licensure of an interchangeable biosimilar under section 351(k) of the PHS 
158  Act, an applicant must show that the product meets the standards described in section 
159  351(k)(4).4  Among the specified criteria that must be met to be licensed as an 
160  interchangeable biosimilar under section 351(k)(4), the applicant must show that the 
 
4 In addition to the requirement under section 351(k)(4) that FDA determine that the information submitted in the 
application or the supplement is sufficient to show that the biological product is biosimilar to the reference 
product, FDA must also find that the proposed product can be expected to produce the same clinical result as the 
reference product in any given patient, and that for a biological product that is administered more than once to an 
individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological 
product and the reference product is not greater than the risk of using the reference product without such alternation 
or switch in order to license the proposed product as an interchangeable biosimilar. 
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161  biological product is biosimilar to the reference product.  Thus, there may be 
162  situations in which the data and information provided in a BLA seeking licensure as 
163  an interchangeable biosimilar can support licensure of the product as a biosimilar 
164  product but not as an interchangeable biosimilar.   
165   
166  As an initial matter, if a BLA submitted under section 351(k) of the PHS Act is 
167  intended to support licensure as an interchangeable biosimilar, the BLA submission 
168  should contain an affirmative statement to that effect.  If a BLA submission does not 
169  contain such a statement, the Agency plans to evaluate the BLA for licensure only as 
170  a biosimilar product.  In other words, the Agency intends to evaluate whether the 
171  proposed product meets the requirements for licensure as an interchangeable 
172  biosimilar only if the 351(k) BLA indicates at the time of submission that it contains 
173  information intended to demonstrate that the product meets the standards described in 
174  section 351(k)(4) for licensure as an interchangeable biosimilar.  This approach 
175  provides for a more efficient and predictable review of BLAs.  
176   
177  If an applicant indicates in its cover letter that a BLA submitted under section 351(k) 
178  contains information intended to demonstrate interchangeability, the Agency 
179  generally plans to evaluate the BLA as both an application for licensure of a 
180  biosimilar product and an application for licensure of an interchangeable biosimilar.  
181  In such cases, if a BLA submitted under section 351(k) contains data and information 
182  sufficient to support licensure of the product as a biosimilar product but does not 
183  contain data and information sufficient to support licensure of the product as an 
184  interchangeable biosimilar as a scientific matter, FDA intends to split the application 
185  for administrative purposes.  This will enable the Agency to take separate actions on 
186  such a BLA as appropriate.  For example, FDA could license the product as a 
187  biosimilar product5 and convey deficiencies in the application for licensure as an 
188  interchangeable biosimilar to the applicant in a complete response letter, and FDA 
189  could make a determination of interchangeability for the product upon submission of 
190  a supplement that contains all data and information necessary to support licensure of 
191  the product as an interchangeable biosimilar.6 
192   
193  However, if an applicant specifically requests that the Agency approve an application 
194  for licensure submitted under 351(k) only if FDA determines the product to be 
195  interchangeable with the reference product, the Agency plans to evaluate only 
196  whether the application for the biological product meets the standards described in 
197  section 351(k)(4) for licensure as an interchangeable biosimilar (an interchangeable-
198  only review).  The Agency recommends that an applicant requesting this type of 
199  review clearly note the request for INTERCHANGEABLE-ONLY REVIEW in the 
200  cover letter accompanying the BLA.  If upon an interchangeable-only review the 
201  Agency determines that a BLA is not approvable for licensure as an interchangeable 
202  biosimilar, the Agency intends to send a complete response letter addressing the 
 
5 Section 351(k)(3) of the PHS Act. 21 CFR 601.4. 
 
6 21 CFR 601.3. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
203  request for licensure as an interchangeable biosimilar.7  The complete response letter 
204  would also include deficiencies pertaining to a demonstration of biosimilarity, if any, 
205  because biosimilarity is a condition necessary for approval of a 351(k) BLA as an 
206  interchangeable product.  Consistent with the applicants request, however, the 
207  complete response letter would not address whether the application was sufficient to 
208  support a demonstration of licensure as a biosimilar product alone.  Upon receipt of 
209  an interchangeable-only complete response letter, the applicant may then choose to 
210  amend and resubmit their application to address the deficiencies and support a 
211  demonstration of interchangeability or to amend and resubmit their BLA seeking 
212  licensure as a biosimilar product.8  
213   
214     
215  Q.I.26  How should a 351(a) BLA holder proceed if it seeks licensure of its biological 
216  product under section 351(k) as biosimilar to or interchangeable with another 
217  biological product licensed under section 351(a) (a reference product)? 
218  [Draft November 2020] 
219   
220  A.I.26 FDA reviews data and information intended to support licensure of a proposed 
221  biological product as a biosimilar product in an original application submitted under 
222  section 351(k) of the PHS Act.9  Similarly, FDA reviews data and information 
223  intended to support licensure of a proposed biological product as an interchangeable 
224  biosimilar in an original application submitted under section 351(k) of the PHS Act or 
225  a supplement to an approved application submitted under section 351(k) of the PHS 
226  Act.10  Therefore, if a holder of a BLA for a biological product licensed or deemed 
227  licensed11 under section 351(a) wishes to submit an application for licensure of that 
228  biological product as a biosimilar to or interchangeable with another biological 
229  product, i.e. the reference product, it should do so by submitting an original 
230  application for licensure under section 351(k). 
231   
232  As with any application under section 351(k), such an application should specify the 
233  single biological product licensed or deemed licensed under section 351(a) of the 
234  PHS Act as the reference product, as that term is defined in section 351(i), against 
235  which the proposed biosimilar or proposed interchangeable product will be evaluated.  
236  The application for licensure under section 351(k) also should include data and 
 
7 See 21 CFR 601.3. 
 
8 See 21 CFR 601.3. 
 
9 See sections 351(k)(2) and (3) of the PHS Act.  See also guidance for industry Scientific Considerations in 
Demonstrating Biosimilarity to a Reference Product (April 2015). 
 
10 See sections 351(k)(3) and (4) of the PHS Act.  See also guidance for industry Considerations in Demonstrating 
Interchangeability With a Reference Product (May 2019) (Interchangeability Guidance). 
 
11 See guidance for industry Interpretation of the Deemed to be a License Provision of the Biologics Price 
Competition and Innovation Act of 2009 (December 2018). 
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
237  information sufficient to demonstrate biosimilarity,12 and, if interchangeability is 
238  sought, interchangeability with the specified reference product.13    
239   
240  An applicant may support a demonstration of biosimilarity or interchangeability 
241  under section 351(k) using relevant data and information from the applicants own 
242  351(a) BLA.  It is not necessary for the holder of a 351(a) BLA for a biological 
243  product licensed or deemed licensed under section 351(a) to seek revocation of its 
244  351(a) license in order to submit a 351(k) application.  The 351(a) BLA holder may 
245  continue to market the biological product licensed or deemed licensed under section 
246  351(a) while the 351(k) BLA is pending and after licensure of the biological product 
247  under section 351(k).14  
248   
249  FDA believes that this approach balances the opportunity for continued innovation 
250  with respect to the biological product licensed or deemed licensed under section 
251  351(a) of the PHS Act while facilitating robust market competition through the 
252  approval of biosimilar and interchangeable products under the 351(k) pathway. 
253   
254   
255  Q.I.27  This question and its answer have been withdrawn.  For information on 
256  labeling for interchangeable biosimilar products, see FDAs draft guidance for 
257  industry Labeling for Biosimilar and Interchangeable Biosimilar Products.15 
258   
259   
260  Q.I.28  This question and its answer have been withdrawn.  For information on 
261  labeling for interchangeable biosimilar products, see FDAs draft guidance for 
262  industry Labeling for Biosimilar and Interchangeable Biosimilar Products.16 
263   
264  II.  PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA FOR A 
265  BIOLOGICAL PRODUCT 
266   
267  There are no draft Q&As for this section. 
 
12 For more information on demonstrating biosimilarity, see draft guidance for industry Development of Therapeutic 
Protein Biosimilars:  Comparative Analytical Assessment and Other Quality-Related Considerations (May 2019) 
(this draft guidance, when finalized, will represent FDAs current thinking on this topic) and guidance for industry 
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015).  
 
13 For more information on interchangeability, see the Interchangeability Guidance.  A biosimilar product or 
interchangeable biosimilar may be licensed only for conditions of use that have been previously approved for the 
reference product.  Section 351(k)(2)(A)(i)(III) of the PHS Act.  See also draft guidance for industry Biosimilars and 
Interchangeable Biosimilars:  Licensure for Fewer Than All Conditions of Use for Which the Reference Product 
Has Been Licensed (February 2020), which, when finalized, will represent FDAs current thinking on the topic. 
 
14 21 CFR 601.5.  Each product would need to be marketed in accordance with its respective approved conditions of 
use, as reflected in each products FDA-approved product labeling. 
 
15 When final, this guidance will represent the FDAs current thinking on this topic. 
 
16 When final, this guidance will represent the FDAs current thinking on this topic. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
268   
269  III.  EXCLUSIVITY 
270   
271  There are no draft Q&As for this section. 
  8