New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 4): Draft Guidance for Industry

Administrative draft guidance, not enacted legislation.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

New and Revised Draft Q&As on
Biosimilar Development and
the BPCI Act (Revision 4)
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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) Division of Drug Information at
(855) 543-3784 or (301) 796-3400, or (CBER) Outreach and Development at 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)
March 2026
Biosimilars
Revision 4

New and Revised Draft Q&As on
Biosimilar Development and
the BPCI Act (Revision 4)
Guidance for Industry
Additional copies are available from:
Division 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)
March 2026
Biosimilars
Revision 4

Contains Nonbinding Recommendations
Draft—Not for Implementation
TABLE OF CONTENTS
INTRODUCTION......................................................................................................................... 1
BACKGROUND ........................................................................................................................... 2
QUESTIONS AND ANSWERS ................................................................................................... 4
I. 	BIOSIMILARITY OR INTERCHANGEABILITY ................................................................. 4
Q.I.8. 	Can a sponsor use comparative clinical data with a non-U.S.-licensed product to support a
demonstration that the proposed product is biosimilar to the reference product? ................ 4
Q.I.10. How long and in what manner should sponsors retain reserve samples of the biological
products used in comparative clinical PK and/or PD studies intended to support a 351(k)
application? .......................................................................................................................... 7
Q.I.12. How can an applicant demonstrate that its proposed injectable biosimilar product or
proposed injectable interchangeable product has the same “strength” as the reference
product? ................................................................................................................................ 8
Q.I.19. If a non-U.S.-licensed comparator product is proposed for importation and use in the
United States in a clinical investigation intended to support licensure of a proposed product
under section 351(k), is a separate IND required for the non-U.S.-licensed product?.......... 9
II. 	PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA FOR A
BIOLOGICAL PRODUCT ......................................................................................................... 11
III. 	EXCLUSIVITY.......................................................................................................................... 11

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
New and Revised Draft Q&As on Biosimilar Development and	1
the BPCI Act (Revision 4)	2
Guidance for Industry13
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 abbreviated licensure pathway in section 351(k) of the	18
Public Health Service Act (PHS Act) (42 U.S.C. 262(k)), which was added by the Biologics	19
Price Competition and Innovation Act of 2009 (BPCI Act). The question and answer (Q&A)	20
format is intended to inform prospective applicants and facilitate the development of proposed	21
biosimilar products and proposed interchangeable products,2 as well as describe FDA’s	22
interpretation of certain statutory requirements.	23
24
Section 351(k) of the PHS Act provides an abbreviated licensure pathway for biological products	25
shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product	26
(see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Public Law	27
111-148) (ACA)). FDA believes that guidance for industry that provides answers to commonly	28
asked questions regarding FDA’s interpretation of section 351(k) of the PHS Act will enhance	29
transparency and facilitate the development and approval of biosimilar and interchangeable	30
products. In addition, these Q&As respond to questions the Agency has received from	31
prospective applicants regarding the submission of biologics license applications (BLAs) for	32
proposed biosimilar and interchangeable products. FDA may provide additional Q&As through	33
draft guidance as appropriate.	34
35
1 This draft 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.
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 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) biologics license application. Biosimilarity, interchangeability, and related issues are discussed in
more detail in the Background section of this guidance.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
This draft guidance revises and replaces the draft guidance for industry New and Revised Draft	36
Q&As on Biosimilar Development and the BPCI Act (Revision 3) (September 2021). The	37
specific changes include:	38
39
• 	Q&A I.8 — revised for public comment with updated content.	40
41
• 	Q&A I.10 and Q&A I.19 — updated with conforming and clarifying revisions and	42
moved from the final guidance for industry Questions and Answers on Biosimilar	43
Development and the BPCI Act (September 2021) (Revision 2) to this draft guidance.	44
45
• 	Q&A I.12 — retained from the draft guidance for industry New and Revised Draft Q&As	46
on Biosimilar Development and the BPCI Act (Revision 3) (September 2021) without	47
change.	48
49
Additional information about the Q&A format for this draft guidance is provided in the	50
Background section.	51
52
After FDA has considered any comments on the revised draft Q&As, the draft Q&As in this	53
guidance will be finalized by adding the Q&As, as a revision, to the final guidance for industry	54
Questions and Answers on Biosimilar Development and the BPCI Act (Revision 3) as	55
appropriate. That final guidance is part of a series of guidances that FDA has developed to	56
facilitate development of biosimilar and interchangeable biosimilar products.3
57
58
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	59
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	60
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	61
the word should in Agency guidances means that something is suggested or recommended, but	62
not required.	63
64
65
BACKGROUND	66
67
The BPCI Act	68
69
The BPCI Act was enacted as part of the ACA on March 23, 2010. The BPCI Act amended the	70
PHS Act and other statutes to create an abbreviated licensure pathway for biological products	71
shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product	72
(see sections 7001 through 7003 of the ACA). Section 351(k) of the PHS Act, added by the	73
BPCI Act, sets forth the requirements for the licensure of a proposed biosimilar or proposed	74
interchangeable product.	75
76
3 To search for specific guidances on biosimilar and interchangeable biosimilar products on the FDA guidance web
page (https://www.fda.gov/regulatory-information/search-fda-guidance-documents), select “Biosimilars” in the topic
field. Additional guidances that are applicable to biological products, including biosimilar and interchangeable
biosimilar products, can be found in other topic areas, such as “Chemistry, Manufacturing, and Controls (CMC)”
and “Administrative/Procedural.”

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
Section 351(i) of the PHS Act defines biosimilarity to mean “that the biological product is highly	77
similar to the reference product notwithstanding minor differences in clinically inactive	78
components” and that “there are no clinically meaningful differences between the biological	79
product and the reference product in terms of the safety, purity, and potency of the product” (see	80
section 351(i)(2) of the PHS Act).	81
82
A BLA submitted under section 351(k) (known as a 351(k) BLA) of the PHS Act must contain,	83
among other things, information demonstrating that the biological product is biosimilar to a	84
reference product based upon data derived from analytical studies, an assessment of toxicity, and	85
a clinical study or studies (see section 351(k)(2)(A)(i)(I) of the PHS Act), unless FDA has	86
determined that an element described in section 351(k)(2)(A)(i)(I) is unnecessary (see section	87
351(k)(2)(A)(ii) of the PHS Act). To meet the standard for interchangeability, an applicant must	88
provide sufficient information to demonstrate biosimilarity to the reference product and also to	89
demonstrate that the biological product can be expected to produce the same clinical result as the	90
reference product in any given patient, and if the biological product is administered more than	91
once to an individual, the risk in terms of safety or diminished efficacy of alternating or	92
switching between the use of the biological product and the reference product is not greater than	93
the risk of using the reference product without such alternation or switch (see section 351(k)(4)	94
of the PHS Act). Interchangeable products may be substituted for the reference product without	95
the intervention of the prescribing health care provider (see section 351(i)(3) of the PHS Act).	96
97
“Question-and-Answer” Guidance Format	98
99
FDA has been using the Q&A guidance format to describe the Agency’s thinking on and update	100
certain information and recommendations relevant to the development of biosimilar and	101
interchangeable products. This draft guidance includes only Q&As that are in draft form. The	102
guidance for industry Questions and Answers on Biosimilar Development and the BPCI Act	103
contains all Q&As that are final. As FDA issues individual Q&As, they will first be	104
incorporated into a draft Q&A guidance. After FDA has considered any comments on draft	105
Q&As received during the relevant comment period and, if warranted, incorporated suggested	106
changes to the Q&As, individual Q&As will be finalized and moved to the final guidance, as	107
appropriate.	108
109
A Q&A that was previously in the final guidance may be withdrawn and moved to a draft	110
guidance if FDA determines that the Q&A should be revised in some respect and reissued in a	111
revised draft Q&A for comment. A Q&A also may be withdrawn and removed from the Q&A	112
guidance if, for instance, the issue addressed in the Q&A is addressed in another FDA guidance.	113
114
FDA will provide the publication date of the current version of each Q&A and information about	115
whether the Q&A has been added to or modified in the relevant draft guidance. FDA has	116
maintained the original numbering of the guidance Q&As used in the final guidance for industry	117
Questions and Answers on Biosimilar Development and the BPCI Act (Revision 2), the draft	118
guidance for industry New and Revised Draft Q&As on Biosimilar Development and the BPCI	119
Act (Revision 3), and the draft guidance for industry Biosimilarity and Interchangeability:	120
Additional Draft Q&As on Biosimilar Development and the BPCI Act (September 2023)	121

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
(Revision 1).4 For ease of reference, a Q&A retains the same number when it moves from a	122
draft guidance to the final guidance and, where appropriate, when a Q&A is withdrawn from the	123
final guidance and moved to a draft guidance.	124
125
When FDA withdraws a Q&A or moves it from draft guidance to final guidance or from final	126
guidance to draft guidance for public comment, it marks the change in the first guidance with	127
several asterisks between nonconsecutive Q&As and provides explanatory text when	128
appropriate.	129
130
131
QUESTIONS AND ANSWERS	132
133
I. 	BIOSIMILARITY OR INTERCHANGEABILITY	134
135
Q.I.8. 	Can a sponsor use comparative clinical data with a non-U.S.-licensed product	136
to support a demonstration that the proposed product is biosimilar to the	137
reference product?	138
[Revised in Draft March 2026]	139
140
A.I.8.a 	Yes, under certain circumstances. If a sponsor seeks to use data from a clinical	141
study comparing its proposed biosimilar product to a non-U.S.-licensed product	142
(“non-U.S.-licensed comparator product”) to address, in part, the requirements	143
under section 351(k)(2)(A) of the PHS Act, the sponsor should provide adequate	144
data or information to scientifically justify why such comparative data are	145
relevant to the assessment of biosimilarity to the U.S.-licensed reference	146
product.	147
148
A scientific justification may be acceptable in circumstances that include:	149
150
• 	The proposed biosimilar product, the U.S.-licensed reference product, and	151
the non-U.S.-licensed comparator product are highly purified therapeutic	152
proteins that can be structurally and functionally characterized with a high	153
degree of specificity and sensitivity using currently available analytical	154
technologies; and	155
156
• 	The applicant submits information that the non-U.S.-licensed comparator	157
product has the same or only minor differences in quantitative and/or	158
qualitative composition of inactive ingredients as the U.S.-licensed	159
reference product that would not be expected to affect clinical	160
performance between the U.S.-licensed reference product and the non-	161
U.S.-licensed comparator product; and	162
163
• 	There is an adequate scientific rationale for why analytical differences (if	164
any) identified in product quality attributes between the non-U.S.-licensed	165
comparator product used in the clinical study and the U.S.-licensed	166
4 When final, this guidance will represent FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
5
reference product included in the applicant’s comparative analytical	167
assessment (described further in part (b) of this response) would not	168
preclude a conclusion that data from a clinical study comparing the	169
proposed biosimilar product to the non-U.S.-licensed comparator product	170
are relevant to a demonstration of biosimilarity to the U.S.-licensed	171
reference product.	172
173
Publicly available information describing the relationship between the U.S.-	174
licensed reference product and the non-U.S.-licensed comparator product would	175
not obviate the need for comparative analytical data to scientifically justify use of	176
a non-U.S.-licensed comparator in a clinical study intended to support a	177
demonstration of biosimilarity to the U.S.-licensed reference product.	178
179
If the above circumstances apply and an adequate scientific justification is	180
provided, a clinical study (such as an assessment of pharmacokinetics) comparing	181
the proposed biosimilar with the non-U.S.-licensed comparator product could	182
address, in part, the requirements under section 351(k)(2)(A) of the PHS Act and	183
support a demonstration of biosimilarity to the U.S.-licensed reference	184
product.5,6
185
186
Issues that a sponsor may need to address to use a non-U.S.-licensed comparator	187
product in a biosimilar development program include the following:	188
189
• 	Whether the non-U.S.-licensed comparator product was manufactured in a	190
facility(ies) licensed and inspected by a regulatory authority that has	191
similar scientific and regulatory standards as FDA (e.g., International	192
Conference on Harmonisation (ICH) countries); and	193
194
• 	Whether the non-U.S.-licensed comparator product was licensed by a	195
regulatory authority that has similar scientific and regulatory standards as	196
FDA (e.g., ICH countries) and the duration and extent to which the	197
product has been marketed.	198
199
Sponsors are encouraged to discuss with FDA any plans (including, but not	200
limited to, the circumstances above) to submit and scientifically justify clinical	201
data derived from non-U.S.-licensed comparator products in support of a 351(k)	202
application as early as feasible during product development. A final decision	203
about the adequacy of the data and information intended to scientifically justify	204
5 The draft guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:
Updated Recommendations for Assessing the Need for Comparative Efficacy Studies (October 2025) is available on
the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. When
final, this guidance will represent the FDA’s current thinking on this topic.
6 Differences in strength or dosage form between the U.S.-licensed reference product and non-U.S.-licensed
comparator product do not necessarily preclude use of the non-U.S.-licensed comparator product in a clinical study
intended to support a demonstration of biosimilarity.

Contains Nonbinding Recommendations
Draft — Not for Implementation
6
the relevance of a non-U.S.-licensed comparator product to the assessment of	205
biosimilarity will be made during review of the 351(k) application.	206
207
A.I.8.b 	Reference Product and Non-U.S.-Licensed Comparator Products7
208
209
For purposes of the comparative analytical assessment and comparison between	210
the non-U.S.-licensed comparator product and the U.S.-licensed reference	211
product, any lots used in a clinical study supporting a demonstration of	212
biosimilarity should be included in the comparative analytical assessment	213
intended to justify the relevance of comparative data with the non-U.S.-licensed	214
comparator product to a demonstration of biosimilarity.8 Specifically, if a clinical	215
study compares the proposed biosimilar to a non-U.S.-licensed comparator	216
product, sponsors should ensure that data generated in that clinical study are	217
relevant and applicable to the demonstration of biosimilarity by providing	218
sufficient comparative analytical data based on: (1) the lots of the non-U.S.-	219
licensed comparator product used in the clinical study; and (2) the lots of the	220
U.S.-licensed reference product used in the comparative analytical assessment to	221
support a demonstration that the proposed biosimilar is highly similar to the U.S.-	222
licensed reference product. If analytical differences are observed between the	223
clinical lots of the non-U.S.-licensed comparator product and the U.S.-licensed	224
reference product lots used in the comparative analytical assessment with the	225
proposed biosimilar, the sponsor may provide information (e.g., a risk assessment	226
and relevant analytical data) to scientifically justify why these differences do not	227
preclude a conclusion that the data from the clinical study comparing the	228
proposed biosimilar to the non-U.S.-licensed comparator product are relevant to	229
the demonstration of biosimilarity.	230
231
The acceptance criteria used to support a demonstration that a proposed biosimilar	232
product is highly similar to the U.S.-licensed reference product should be derived	233
from data generated from a sponsor’s analysis of the U.S.-licensed reference	234
product. The comparative analytical assessment should be based on a direct	235
comparison of the proposed biosimilar product to the U.S.-licensed reference	236
product. As a scientific matter, combining data from the U.S.-licensed reference	237
product and non-U.S.-licensed comparator product to determine the acceptance	238
criteria or to perform the comparative analytical assessment for the proposed	239
product would not be acceptable to support a demonstration that the proposed	240
product is biosimilar to the U.S.-licensed reference product.	241
7 This draft guidance is not intended to be finalized in the guidance for industry Questions and Answers on
Biosimilar Development and the BPCI Act (Revision 3). Instead, the recommendations in this draft guidance, after
considering any comments received in the docket, are intended to inform future revisions to the guidance for
industry Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-
Related Considerations (September 2025) such as changes to recommendations in section VI.A.3 related to the
subject addressed in this guidance.
8 For additional information on the comparative analytical assessment, see section VI of the guidance for industry
Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related
Considerations (September 2025).

Contains Nonbinding Recommendations
Draft — Not for Implementation
7
242
Sponsors are encouraged to discuss with FDA any plans to submit clinical data	243
derived from a study using a non-U.S.-licensed comparator product in support of	244
a 351(k) application as early as feasible during product development. A final	245
decision about the adequacy of the data and information intended to scientifically	246
justify the relevance of a non-U.S.-licensed comparator product to the assessment	247
of biosimilarity will be made during review of the 351(k) application.	248
249
* * * * *	250
251
Q.I.10. 	How long and in what manner should sponsors retain reserve samples of the	252
biological products used in comparative clinical PK and/or PD studies intended	253
to support a 351(k) application?	254
[Revised in Draft March 2026]	255
256
A.I.10. 	Reserve samples establish the identity of the products tested in the actual study,	257
allow for confirmation of the validity and reliability of the results of the study,	258
and facilitate investigation of further follow-up questions that arise after the	259
studies are completed. FDA recommends that the sponsor of a proposed	260
biosimilar product retain reserve samples for at least 5 years following the date on	261
which the 351(k) application is licensed, or, if such application is not licensed, at	262
least 5 years following the date of completion of a comparative clinical	263
pharmacokinetic (PK) and/or pharmacodynamic (PD) study of the reference	264
product and the proposed biosimilar product (or other clinical study in which PK	265
or PD samples are collected with the primary objective of assessing PK or PD	266
similarity) that is intended to support a submission under section 351(k) of the	267
PHS Act. Contact FDA for specific advice if an alternative approach is being	268
considered. For a PK similarity study, FDA recommends that samples of the	269
proposed biosimilar and the reference product or, if applicable, non-U.S.-licensed	270
comparator product be retained.	271
272
For most protein therapeutics, FDA recommends that a sponsor retain the	273
following quantities of product and dosage units, which are expected to be	274
sufficient for evaluation by state-of-the-art analytical methods:	275
276
• 	A minimum of 10 dosage units each of the proposed biosimilar product,	277
reference product and, if applicable, non-U.S.-licensed comparator	278
product, depending on the amount of product within each unit; in general,	279
this should provide for a total product mass of equal to or greater than 200	280
milligrams (mg) in a volume equal to or greater than 10 milliliters (mL).	281
282
FDA recommends that the sponsor contact the review division to discuss the	283
appropriate quantities of reserve samples in the following situations:	284
285
• 	A product mass of equal to or greater than 200 mg in a volume equal to or	286
greater than 10 mL requires a large number of dosage units	287

Contains Nonbinding Recommendations
Draft — Not for Implementation
8
288
• 	Biological products other than protein therapeutics	289
290
* * * * *	291
292
Q.I.12. 	How can an applicant demonstrate that its proposed injectable biosimilar product	293
or proposed injectable interchangeable product has the same “strength” as the	294
reference product?	295
[Draft December 2018]	296
297
A.I.12. Under section 351(k)(2)(A)(i)(IV) of the PHS Act, an applicant must	298
demonstrate that the “strength” of the proposed biosimilar product or proposed	299
interchangeable product is the same as that of the reference product. Data and	300
information generated as part of the analytical similarity assessment may inform	301
the determination that a proposed biosimilar product or proposed interchangeable	302
product has the same strength as its reference product. As a scientific matter, there	303
may be a need to take into account different factors and approaches in	304
determining the strength of different biological products. Sponsors should discuss	305
their proposed approach with FDA and provide an adequate scientific basis for	306
their approach to demonstrating same strength.	307
308
In general, a sponsor of a proposed biosimilar product or proposed	309
interchangeable product with an injection dosage form (e.g., a solution) can	310
demonstrate that its product has the same strength as the reference product by	311
demonstrating that both products have the same total content of drug substance (in	312
mass or units of activity) and the same concentration of drug substance (in mass	313
or units of activity per unit volume). In general, for a proposed biosimilar product	314
or proposed interchangeable product that is a dry solid (e.g., a lyophilized	315
powder) from which a constituted or reconstituted solution is prepared, a sponsor	316
can demonstrate that the product has the same strength as the reference product by	317
demonstrating that both products have the same total content of drug substance (in	318
mass or units of activity).	319
320
Although not a part of demonstrating same strength, if the proposed biosimilar	321
product or proposed interchangeable product is a dry solid (e.g., a lyophilized	322
powder) from which a constituted or reconstituted solution is prepared, the 351(k)	323
application generally should contain information that the concentration of the	324
proposed biosimilar product or proposed interchangeable product, when	325
constituted or reconstituted, is the same as that of the reference product, when	326
constituted or reconstituted.	327
328
A sponsor should determine the content of drug substance for both the reference	329
product and the proposed biosimilar product or proposed interchangeable product	330
using the same method. The strength of the proposed product generally should be	331
expressed using the same units of measure as the reference product.	332
333

Contains Nonbinding Recommendations
Draft — Not for Implementation
9
* * * * *	334
335
Q.I.19. 	If a non-U.S.-licensed comparator product is proposed for importation and use	336
in the United States in a clinical investigation intended to support licensure of a	337
proposed product under section 351(k), is a separate IND required for the non-	338
U.S.-licensed product?	339
[Revised in Draft March 2026]	340
341
A.I.19. 	A sponsor may submit a single investigational new drug application (IND) for a	342
development program that is intended to support licensure of a proposed product	343
under section 351(k) of the PHS Act and includes use of a non-U.S.-licensed	344
comparator product. The sponsor should submit information supporting the	345
proposed clinical investigation with the non-U.S.-licensed comparator product	346
under the IND. This scenario may occur if a sponsor seeks to use data from a	347
clinical study comparing its proposed biosimilar product to a non-U.S.-licensed	348
comparator product to address, in part, the requirements under section	349
351(k)(2)(A) of the PHS Act. For example, a sponsor may propose to conduct a	350
clinical PK study in the United States with the proposed biosimilar product and a	351
non-U.S.-licensed comparator product.	352
353
A non-U.S.-licensed comparator product is considered an investigational new drug	354
in the United States, and thus would require an IND for importation and use in the	355
United States (see 21 CFR 312.110(a)). If a sponsor intends to conduct a clinical	356
investigation in the United States using a non-U.S.-licensed comparator product,	357
the IND requirements in 21 CFR part 312 also would apply to this product (see,	358
e.g., 21 CFR 312.2).	359
360
With respect to chemistry, manufacturing, and controls (CMC) information, a	361
sponsor should submit to the IND as much of the CMC information required by 21	362
CFR 312.23(a)(7) as is available. However, FDA recognizes that a sponsor may	363
not be able to obtain all the CMC information required by 21 CFR 312.23(a)(7) for	364
a non-U.S.-licensed comparator product for which it is not the manufacturer. In	365
these circumstances, the sponsor can request in an IND submission that FDA	366
waive the regulatory requirements related to CMC information on the non-U.S.-	367
licensed comparator product (21 CFR 312.10). The waiver request must include at	368
least one of the following:	369
370
• 	An explanation why compliance with the requirements of 21 CFR	371
312.23(a)(7) is unnecessary or cannot be achieved	372
373
• 	Information that will satisfy the purpose of the requirement by helping to	374
ensure that the investigational new drug will have the proper identity,	375
strength, quality, and purity	376
377

Contains Nonbinding Recommendations
Draft — Not for Implementation
10
• 	Other information justifying a waiver9
378
379
Information that is relevant to whether the investigational new drug will have the	380
proper identity, strength, quality, and purity may include, for example,	381
information indicating whether the investigational new drug has been licensed by	382
a regulatory authority that has similar scientific and regulatory standards as FDA,	383
and whether the manufacturing facilities have been inspected by a regulatory	384
authority that has similar scientific and regulatory standards as FDA, (e.g., ICH	385
countries). This should include, to the greatest extent possible, summary approval	386
information and current product labeling made public by the foreign regulatory	387
authority. In addition, a sponsor should also provide information on the	388
conditions and containers that will be used to transport the drug product to the	389
U.S. clinical site(s) and information on the relabeling and repackaging operations	390
that will be used to relabel the drug product for investigational use. This should	391
include information on how exposure of the product to light and temperature	392
conditions outside of the recommended storage conditions will be prevented. A	393
risk assessment on the impact the relabeling operations may have on drug product	394
stability should also be included.	395
396
The sponsor should consult with the appropriate FDA review division regarding	397
the CMC information necessary to support the proposed clinical study.	398
399
As would be applicable to all investigational new drugs, FDA reminds sponsors	400
that the investigator brochure (IB) for studies to be conducted under the IND	401
should be carefully prepared to ensure that it is not misleading, erroneous, or	402
materially incomplete, which can be a basis for a clinical hold (see 21 CFR	403
312.42(b)(1)(iii) and (b)(2)(i)). For example, the term reference product should	404
be used in the IB only to refer to the single biological product licensed under	405
section 351(a) of the PHS Act against which the proposed product is evaluated for	406
purposes of submitting a 351(k) application.	407
408
The IB and study protocol(s) should use consistent nomenclature that clearly	409
differentiates the proposed product from the reference product. Additionally, the	410
IB and study protocol(s) should both clearly describe whether the comparator	411
used in each study is the U.S.-licensed reference product or a non-U.S.-licensed	412
comparator product and use consistent nomenclature that clearly differentiates	413
these products. If a non-U.S.-licensed comparator product is being used in a	414
study conducted in the United States, the IB and study protocol(s) should clearly	415
convey that the product is not FDA-approved and is considered an investigational	416
new drug in the United States. The IB and study protocol(s) also should avoid	417
conclusory statements regarding regulatory determinations (e.g., “comparable,”	418
“biosimilar,” “interchangeable,” “highly similar”) that have not been made.	419
420
* * * * *	421
422
9 See 21 CFR 312.10(a).

Contains Nonbinding Recommendations
Draft — Not for Implementation
11
423
II. 	PROVISIONS RELATED TO REQUIREMENTS TO SUBMIT A BLA	424
FOR A BIOLOGICAL PRODUCT	425
426
There are no draft Q&As for this section.	427
428
429
III. 	EXCLUSIVITY	430
431
There are no draft Q&As for this section.	432