Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed
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Press Release[/caption]
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit 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 listed in the notice of availability that publishes in the Federal Register.
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)
February 2020
Biosimilars
Biosimilars and Interchangeable
Biosimilars: Licensure for Fewer Than
All Conditions of Use for Which the
Reference Product Has Been Licensed
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
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologicsguidances
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)
February 2020
Biosimilars
Contains Nonbinding Recommendations
Draft ? Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
A. The Biosimilar Pathway ................................................................................................................ 2
B. Licensure of a Biosimilar or Interchangeable Biosimilar for Fewer Than All of the
Reference Product?s Licensed Conditions of Use........................................................................ 3
III. RECOMMENDATIONS FOR APPLICANTS SEEKING LICENSURE OF A
BIOSIMILAR OR INTERCHANGEABLE BIOSIMILAR FOR FEWER THAN
ALL OF THE REFERENCE PRODUCT?S LICENSED CONDITIONS OF USE ... 4
A. Submission of Original 351(k) BLA or Supplement to a 351(k) BLA....................................... 4
1. Submission of an Original 351(k) BLA for Licensure for Fewer Than All of the Reference
Product?s Licensed Conditions of Use ...................................................................................... 4
2. Submission of a Supplement to a 351(k) BLA Seeking Licensure of a Biosimilar or
Interchangeable Biosimilar for an Additional Condition of Use Previously Licensed for the
Reference Product ..................................................................................................................... 5
B. Development of Draft Labeling for a Proposed Biosimilar or Interchangeable Product for
Fewer Than All of the Reference Product?s Licensed Conditions of Use ................................. 5
1. Content of Draft Labeling ......................................................................................................... 5
2. Information to Support Draft Labeling for a Biosimilar or Interchangeable Product for
Fewer Than All of the Reference Product?s Licensed Conditions of Use ................................. 6
C. Timing Considerations for Submission of a 351(k) BLA or Supplement to a 351(k) BLA ..... 6
1. Targeted Timelines for Review.................................................................................................. 7
2. Unexpired Exclusivity................................................................................................................ 8
3. Circumstances Other Than Exclusivity, Including Patents ....................................................... 8
Contains Nonbinding Recommendations
Draft?Not for Implementation
1 Biosimilars and Interchangeable Biosimilars: Licensure for Fewer
2 Than All Conditions of Use for Which the Reference Product Has
3 Been Licensed
4 Guidance for Industry1
5
6
7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
11 for this guidance as listed on the title page.
12
13
14
15 I. INTRODUCTION
16
17 This guidance provides recommendations to applicants seeking licensure under section 351(k) of
18 the Public Health Service (PHS) Act of a proposed biosimilar or proposed interchangeable
19 biosimilar2
for fewer than all of the reference product?s licensed conditions of use. This
20 guidance also provides recommendations on the submission of a supplement to a licensed 351(k)
21 biologics license application (BLA) seeking to add a condition of use that previously has been
22 licensed3
for the reference product to the labeling4
of a licensed biosimilar or interchangeable
23 product, including considerations related to the timing of such submissions.
24
25 This guidance includes recommendations regarding the following specific issues:
26
27 ? Submission of an application seeking licensure of a proposed biosimilar or proposed
28 interchangeable biosimilar for fewer than all of the reference product?s licensed conditions of
29 use.
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). 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,
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).
Biosimilarity, interchangeability, and related issues are discussed in more detail in section II of this draft guidance.
3
As stated in FDA?s guidance for industry Considerations in Demonstrating Interchangeability With a Reference
Product (May 2019), FDA expects that applicants seeking to demonstrate interchangeability will submit data and
information to support a showing that the proposed interchangeable product can be expected to produce the same
clinical result as the reference product in all of the reference product?s licensed conditions of use. We update
guidances periodically. For the most recent version of a guidance, check the FDA Drugs guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 4
Unless otherwise specified, the terms biosimilar product labeling and labeling as used in this guidance address
only the prescribing information as described in 21 CFR 201.56 and 201.57.
1
Contains Nonbinding Recommendations
Draft?Not for Implementation
30 ? Development of proposed labeling when the applicant seeks licensure of a proposed
31 biosimilar or proposed interchangeable product for fewer than all of the reference product?s
32 licensed conditions of use.
33 ? Submission of a supplement to an application for a biosimilar or interchangeable biosimilar
34 to seek licensure for a condition of use previously licensed for the reference product. This
35 may occur, for example, when (1) the biosimilar or interchangeable product was initially
36 licensed for fewer than all of the reference product?s licensed conditions of use, or (2) the
37 reference product is licensed for a new condition of use after licensure of the biosimilar or
38 interchangeable product.
39 ? Timing for the submission of a 351(k) BLA or supplement to a licensed 351(k) BLA
40 described above with the goal of obtaining licensure of a condition of use for a biosimilar or
41 interchangeable product as soon as possible after the expiration of any relevant exclusivity or
42 patents.
43
44 This guidance is one in a series of guidances that FDA is developing to implement the Biologics
45 Price Competition and Innovation Act of 2009 (BPCI Act) and includes references to
46 information from other FDA guidances, where appropriate.
47
48 In general, FDA?s guidance documents do not establish legally enforceable responsibilities.
49 Instead, guidances describe the Agency?s current thinking on a topic and should be viewed only
50 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
51 the word should in Agency guidances means that something is suggested or recommended, but
52 not required.
53
54
55 II. BACKGROUND
56
57 A. The Biosimilar Pathway
58
59 Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI Act, sets forth the
60 requirements for the licensure of a biosimilar or interchangeable biosimilar. Section 351(i)
61 defines biosimilarity to mean ?that the biological product is highly similar to the reference
62 product notwithstanding minor differences in clinically inactive components? and that ?there are
63 no clinically meaningful differences between the biological product and the reference product in
64 terms of the safety, purity, and potency of the product? (section 351(i)(2) of the PHS Act). A
65 BLA submitted under section 351(k) (a ?351(k) BLA?) must contain, among other things,
66 information demonstrating that the biological product is biosimilar to a reference product based
67 upon data derived from analytical studies, animal studies,5
and a clinical study or studies, unless
68 FDA determines, in its discretion, that certain studies are unnecessary in a 351(k) BLA (see
69 section 351(k)(2) of the PHS Act).
70
5
We support the principles of the ?3Rs,? to reduce, refine, and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency
to an animal test method.
2
Contains Nonbinding Recommendations
Draft?Not for Implementation
71 To meet the standard for ?interchangeability,? an applicant must provide sufficient information
72 to demonstrate biosimilarity to the reference product and also to demonstrate that the biological
73 product can be expected to produce the same clinical result as the reference product in any given
74 patient and, if the biological product is administered more than once to an individual, the risk in
75 terms of safety or diminished efficacy of alternating or switching between the use of the
76 biological product and the reference product is not greater than the risk of using the reference
77 product without such alternation or switch (see section 351(k)(4) of the PHS Act).
78 Interchangeable biosimilars may be substituted for the reference product without the intervention
79 of the prescribing healthcare provider (see section 351(i)(3) of the PHS Act).
80
81 B. Licensure of a Biosimilar or Interchangeable Biosimilar for Fewer Than All of the
82 Reference Product?s Licensed Conditions of Use
83
84 A biosimilar or interchangeable biosimilar may be licensed only for conditions of use that have
85 been previously licensed for the reference product.6
An applicant generally may obtain licensure
86 of a biosimilar or interchangeable for fewer than all of the conditions of use for which the
87 reference product is licensed.7
However, FDA recommends that an applicant seeking licensure
88 for a proposed interchangeable product seek licensure for all of the reference product?s licensed
89 conditions of use when possible.8
90
91 A variety of circumstances may lead an applicant to seek licensure of a proposed biosimilar or
92 proposed interchangeable product for fewer than all of the conditions of use for which the
93 reference product is licensed. Examples of these circumstances are described below.
94
95 Orphan-drug Exclusivity
96
97 The reference product may be licensed for one or more indications that are protected by orphan98 drug exclusivity. In such cases, until the applicable exclusivity expires, FDA will not be able to
99 license a biosimilar or interchangeable product for the protected indications. However, assuming
100 that the requirements for licensure are met, FDA may be able to license a biosimilar or
101 interchangeable product for one or more indications of the reference product that are not
102 protected by orphan-drug exclusivity. In such circumstances, an applicant may choose to seek
103 licensure of a biosimilar or interchangeable product for such indications.
104
105 After the applicable orphan-drug exclusivity expires, the applicant may, in a supplement to the
106 licensed 351(k) BLA, seek licensure of the biosimilar or interchangeable biosimilar for a
6
Section 351(k)(2)(A)(i)(III) of the PHS Act.
7 Notably, section 351(k)(4)(A) of the PHS Act provides, among other things, that an application for an
interchangeable product must include information sufficient to show that the proposed interchangeable product ?can
be expected to produce the same clinical result as the reference product in any given patient.? FDA expects that
applicants seeking to demonstrate interchangeability will submit data and information to support a showing that the
proposed interchangeable product can be expected to produce the same clinical result as the reference product in all
of the reference product?s licensed conditions of use. Guidance for industry Considerations in Demonstrating
Interchangeability With a Reference Product (May 2019).
8
Guidance for industry Considerations in Demonstrating Interchangeability With a Reference Product (May 2019).
3
Contains Nonbinding Recommendations
Draft?Not for Implementation
107 previously protected indication, and FDA may license the biosimilar or interchangeable
108 biosimilar for this indication if the requirements for licensure are met.9
109
110 Circumstances Other Than Exclusivity
111
112 ? Patent(s) covering a licensed condition of use of the reference product: An applicant may
113 conclude that a licensed condition of use of the reference product is protected by one or more
114 patent(s). As a result, the applicant may decide not to seek licensure of a proposed biosimilar
115 or proposed interchangeable product for conditions of use that are protected by patent,
116 according to the applicant?s own assessment.
117
118 ? Other reasons: Reasons other than patents or exclusivity may lead an applicant to choose to
119 seek licensure for fewer than all conditions of use for which the reference product is licensed.
120
121 III. RECOMMENDATIONS FOR APPLICANTS SEEKING LICENSURE OF A
122 BIOSIMILAR OR INTERCHANGEABLE BIOSIMILAR FOR FEWER THAN
123 ALL OF THE REFERENCE PRODUCT?S LICENSED CONDITIONS OF USE
124
125 A. Submission of Original 351(k) BLA or Supplement to a 351(k) BLA
126
127 1. Submission of an Original 351(k) BLA for Licensure for Fewer Than All of the
128 Reference Product?s Licensed Conditions of Use
129
130 As part of an original 351(k) BLA, an applicant is expected to submit draft labeling that includes
131 the conditions of use for which the applicant is seeking licensure of the proposed biosimilar or
132 proposed interchangeable product.10, 11 Additional considerations regarding draft labeling are
133 described in section III.B in this guidance. Applicants may contact the appropriate review
134 division in FDA for more information about submitting a 351(k) BLA for licensure of a
135 proposed biosimilar or proposed interchangeable biosimilar for fewer than all of the reference
136 product?s licensed conditions of use.
137
9
Similarly, as provided by section 351(m) of the PHS Act, an additional six-month period of exclusivity will attach
to certain applicable periods of exclusivity if the sponsor conducts pediatric studies that meet the requirements for
pediatric exclusivity pursuant to section 505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). As with
orphan-drug exclusivity, during the applicable period of pediatric exclusivity FDA may be able to license a
biosimilar or interchangeable product for one or more indications of the reference product that are not protected by
such exclusivity, and FDA may license the biosimilar or interchangeable biosimilar for a previously protected
indication after the applicable pediatric exclusivity expires.
10 FDA has issued draft guidance regarding the submission of data and information to support approval of a
proposed biosimilar or interchangeable product for an indication for which the reference product has unexpired
exclusivity. See Q.I.24 in the draft guidance for industry New and Revised Draft Q&As on Biosimilar Development
and the BPCI Act (Revision 2) (December 2018). When finalized, this guidance will represent FDA?s current
thinking on this topic.
11 See section 351(k)(2)(A)(i)(III) of the PHS Act, which requires that a 351(k) application include information
demonstrating that the condition or conditions of use prescribed, recommended, or suggested in the labeling
proposed for the biological product have been previously approved for the reference product.
4
Contains Nonbinding Recommendations
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138 2. Submission of a Supplement to a 351(k) BLA Seeking Licensure of a Biosimilar or
139 Interchangeable Biosimilar for an Additional Condition of Use Previously Licensed
140 for the Reference Product
141
142 The holder of a licensed 351(k) BLA may, in a supplement to the 351(k) BLA, seek licensure of
143 its biosimilar or interchangeable biosimilar for an additional condition of use that has been
144 previously licensed for the reference product and for which the applicant did not originally seek
145 licensure. A 351(k) BLA holder seeking licensure for an additional condition of use must submit
146 a supplement in accordance with 21 CFR 601.12 seeking licensure of the proposed change. See
147 section III.C.
148
149 A supplement to a 351(k) BLA seeking licensure of a biosimilar or interchangeable biosimilar
150 for an additional condition of use should contain all the data and information needed to support
151 licensure of the biosimilar or interchangeable biosimilar for the proposed condition of use, which
152 may include reference to data and information previously submitted to the 351(k) BLA with
153 appropriate scientific justification. Applicants may contact the appropriate clinical review
154 division at FDA for more information about licensure of a biosimilar or interchangeable
155 biosimilar in such circumstances.
156
157 B. Development of Draft Labeling for a Proposed Biosimilar or Interchangeable
158 Product for Fewer Than All of the Reference Product?s Licensed Conditions of Use
159 FDA?s guidance for industry Labeling for Biosimilar Products (?Biosimilar Labeling
160 Guidance?), provides general recommendations on the development of draft labeling for
161 proposed biosimilar products for submission in a 351(k) BLA.12 In the Biosimilar Labeling
162 Guidance, FDA recommends that labeling for a biosimilar product incorporate relevant data and
163 information from the reference product labeling, with appropriate modifications. The Biosimilar
164 Labeling Guidance also explains that determining which data and information from the reference
165 product labeling should be incorporated into the proposed labeling for a biosimilar will depend
166 on whether the applicant is seeking licensure for all?or fewer than all?of the conditions of use
167 licensed for the reference product.
168
169 1. Content of Draft Labeling
170
171 The applicant should develop draft labeling for the proposed biosimilar or proposed
172 interchangeable biosimilar that includes information from the reference product labeling that is
173 relevant to the proposed conditions of use for the proposed biosimilar or interchangeable, with
174 appropriate modifications. In preparing such draft labeling, the applicant should carefully
175 scrutinize the content of all sections of the labeling to ensure that relevant information is
12 See guidance for industry Labeling for Biosimilar Products (July 2018), which states that it does not provide
specific labeling recommendations for interchangeable products and that any specific recommendations for
interchangeable products will be provided in future guidance.
5
Contains Nonbinding Recommendations
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176 included, based on the proposed conditions of use for the proposed biosimilar or interchangeable
177 product.13
178
179 FDA will evaluate the labeling to determine whether it complies with applicable requirements.14
180 For example, the labeling must summarize the essential scientific information needed for the safe
181 and effective use of the product.15 FDA regulations also require that prescription drug labeling
182 contain:
183
184 ?adequate information ? including indications, effects, dosages, routes, methods,
185 and frequency and duration of administration and any relevant warnings, hazards,
186 contraindications, side effects, and precautions, under which practitioners licensed
187 by law to administer the drug can use the drug safely and for the purposes for
188 which it is intended ??16
189
190 2. Information to Support Draft Labeling for a Biosimilar or Interchangeable Product
191 for Fewer Than All of the Reference Product?s Licensed Conditions of Use
192
193 In general, FDA does not expect an applicant to submit a justification for the applicant?s decision
194 not to seek licensure of a biosimilar for all of the reference product?s licensed conditions of use.
195 FDA does not consider the applicability of patents to a proposed biosimilar product (e.g., the
196 validity or enforceability of patents or potential infringement) in its review of a 351(k) BLA or
197 supplement to a 351(k) BLA.17 An applicant seeking licensure of a biosimilar or interchangeable
198 biosimilar for fewer than all of the reference product?s licensed conditions of use may, in a
199 351(k) BLA or a supplement to a 351(k) BLA, submit information that is intended to inform
200 FDA?s review of the draft labeling. For example, an applicant may submit a justification as to
201 why, in the applicant?s view, the draft labeling meets the requirements for approval, considering
202 the conditions of use for which the applicant is seeking licensure.
203
204 C. Timing Considerations for Submission of a 351(k) BLA or Supplement to a 351(k)
205 BLA
206
207 The recommendations in this section are intended to facilitate submission of a 351(k) BLA or
208 supplement to a licensed 351(k) BLA with the goal of obtaining licensure of a biosimilar or
209 interchangeable biosimilar soon after expiration of any relevant exclusivity or expiration of a
13 For example, as noted in the guidance for industry Labeling for Biosimilar Products (July 2018), ?in certain
circumstances it may be necessary to include information in the biosimilar product labeling relating to an
indication(s) for which the biosimilar product is not licensed, in order to help ensure safe use ?? Additionally,
although biosimilar labeling need not be identical to reference product labeling, deviations should be carefully
considered to ensure that the condition or conditions of use prescribed, recommended, or suggested in the draft
labeling for the proposed biosimilar product have been previously approved for the reference product (see section
351(k)(2)(A)(i)(III) of the PHS Act).
14 See, e.g., 21 CFR 201.56 and 21 CFR 201.57.
15 See 21 CFR 201.100 and 201.56(a)(1).
16 See 21 CFR 201.100(d)(1) (emphasis added).
17 For more information about the exchange of confidential information for purposes of determining whether a claim
of patent infringement could reasonably be asserted against a 351(k) applicant, refer to section 351(l) of the PHS Act
(42 U.S.C. 262(l)).
6
Contains Nonbinding Recommendations
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210 patent that, in the 351(k) applicant?s assessment, protects a licensed condition of use of the
211 reference product. These recommendations also are applicable to a supplement to a licensed
212 351(k) BLA that seeks licensure of a biosimilar or interchangeable biosimilar for an additional
213 condition of use for which the applicant did not originally seek licensure but that has since been
214 licensed for the reference product.
215
216 1. Targeted Timelines for Review
217
218
219
220
Original 351(k) BLA
As described in the Biosimilar User Fee Act (BsUFA) II Goals Letter, FDA is committed to
reviewing and acting on original 351(k) BLAs within 10 months of the 60-day filing date.18
221
222
223
224
Supplements to a Licensed 351(k) BLA
In the BsUFA II Goals Letter, FDA also committed to reviewing and acting on original 351(k)
BLA supplements with clinical data within 10 months of receipt.19 In light of the anticipated
225 FDA review burden (among other considerations), FDA anticipates that it will review and act on
226 many supplements seeking licensure for additional conditions of use for a licensed biosimilar or
227 interchangeable product before the BsUFA goal date. To the extent practicable, FDA intends
228 that a supplement to a licensed 351(k) BLA seeking licensure of the biosimilar or
229 interchangeable product for an additional condition of use that has been previously licensed for
230 the reference product will be reviewed and acted upon in a 6-month timeframe, without regard to
231 whether the biosimilar or interchangeable product was initially licensed for fewer than all of the
232 reference product?s licensed conditions of use or the reference product is licensed for a new
233 condition of use after licensure of the biosimilar or interchangeable product.
234
235 FDA recognizes that targeting a 6-month timeline for such supplements may surpass, in many
236 cases, the performance goal commitment FDA made in the BsUFA II Goals Letter. Supplements
237 seeking licensure for additional conditions of use for a licensed biosimilar or interchangeable
238 product likely will include clinical data or reference clinical data submitted previously to the
239 351(k) BLA. As noted, the BsUFA II Goals Letter describes a 10-month goal date for original
240 351(k) BLA supplements with clinical data. However, at this time, FDA believes that a review
241 timeframe of 6 months will generally be appropriate for a supplement to a licensed 351(k) BLA
242 seeking licensure of the biosimilar or interchangeable product for an additional condition of use
243 that has been previously licensed for the reference product, assuming the supplement does not
244 raise novel review issues. Among other considerations, this is based on the anticipated FDA
245 review burden associated with these types of supplements. FDA intends to notify applicants in
246 an acknowledgement letter if it believes that the 10-month review timeline described in the
247 BsUFA II Goals Letter is more appropriate for any such supplement.
248
249
18 See Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018
through 2022 (?BsUFA II Goals Letter?) at https://www.fda.gov/media/100573/download. 19 See BsUFA II Goals Letter.
7
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Draft?Not for Implementation
250 2. Unexpired Exclusivity
251
252
253
The Agency cannot license a biosimilar or interchangeable product for an indication protected by
orphan-drug exclusivity or pediatric exclusivity until the expiration of that exclusivity.20 If an
254 applicant?s proposed labeling includes conditions of use that are protected by unexpired orphan255
256
drug exclusivity or unexpired pediatric exclusivity, the Agency may communicate this issue to
the applicant in the Day 74 letter.21 In these circumstances, an applicant may seek to time the
257 submission of a 351(k) BLA or supplement to a 351(k) BLA with the goal of obtaining licensure
258 after a specific date, such as the expiration of orphan-drug or pediatric exclusivity.
259
260 3. Circumstances Other Than Exclusivity, Including Patents
261
262 As described above, an applicant may choose to seek licensure of a proposed biosimilar or
263 interchangeable biosimilar for fewer than all of the reference product?s licensed conditions of use
264 based on an assessment by the applicant that one or more of the reference product?s licensed
265 conditions of use is protected by patent. In these circumstances, an applicant may seek to time
266 the submission of a 351(k) BLA or supplement to a 351(k) BLA with the goal of obtaining
267 licensure after a specific date, such as the expiration of a patent. Other nonpatent reasons may
268 also lead an applicant to take this approach.
269
270 In contrast to orphan-drug and pediatric exclusivity, the BPCI Act does not limit FDA?s ability to
271 license a 351(k) BLA or a supplement to a 351(k) BLA where a biosimilar seeks licensure for a
272 condition of use which may be subject to one or more patents. FDA may therefore license the
273 product for such condition of use if FDA determines that the requirements for licensure have
274 been met.
275
276
277
Applicants should be aware that FDA may review and act on (i.e., license or issue a complete
response letter to)22 a 351(k) BLA or supplement to a 351(k) BLA before any applicable BsUFA
278 goal date or 6-month targeted review timeline. If an applicant does not want FDA to take action
279 on a 351(k) BLA or supplement to a 351(k) BLA before a specified date, the applicant should
280 request that the Agency refrain from acting on the BLA or supplement before the specified date,
281 so long as that date falls on or before the applicable BsUFA goal date.
282
283 To request that FDA not take action on a 351(k) BLA or supplement to a 351(k) BLA before a
284 specified date, the applicant should include the following language on the cover letter of their
285 BLA or supplement, in bold typeface and prominently placed above the body of the cover letter:
286
287
288
351(k) BLA action timing request: [Applicant Name] requests that FDA not
take action on this [application/supplement] before [specified date].
289
290 If the applicant requests that FDA refrain from taking action on the 351(k) BLA or a supplement
291 to a 351(k) BLA until a specified date that is on or before any applicable BsUFA goal date, the
20 See section 527 of the FD&C Act; section 351(m) of the PHS Act; 21 CFR 316.31. 21 See BsUFA II Goals Letter, p. 10. 22 See BsUFA II Goals Letter, p. 32 (defining ?review and act on? to mean ?the issuance of a complete action letter
after complete review of a filed complete application?).
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292 Agency intends to honor the applicant?s request, where appropriate. Applicants should take
293 BsUFA goal dates into consideration before making such requests. If the requested date extends
294 beyond any applicable BsUFA goal date, the Agency does not intend to honor the applicant?s
295 request.
296
297 Upon receipt of the 351(k) BLA or supplement to a 351(k) BLA containing a request not to act
298 before any applicable BsUFA goal date (or another specified date prior to a BsUFA goal date),
299 FDA int
Press Release[/caption]
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit 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 listed in the notice of availability that publishes in the Federal Register.
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)
February 2020
Biosimilars
Biosimilars and Interchangeable
Biosimilars: Licensure for Fewer Than
All Conditions of Use for Which the
Reference Product Has Been Licensed
Guidance for Industry
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologicsguidances
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)
February 2020
Biosimilars
Contains Nonbinding Recommendations
Draft ? Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
A. The Biosimilar Pathway ................................................................................................................ 2
B. Licensure of a Biosimilar or Interchangeable Biosimilar for Fewer Than All of the
Reference Product?s Licensed Conditions of Use........................................................................ 3
III. RECOMMENDATIONS FOR APPLICANTS SEEKING LICENSURE OF A
BIOSIMILAR OR INTERCHANGEABLE BIOSIMILAR FOR FEWER THAN
ALL OF THE REFERENCE PRODUCT?S LICENSED CONDITIONS OF USE ... 4
A. Submission of Original 351(k) BLA or Supplement to a 351(k) BLA....................................... 4
1. Submission of an Original 351(k) BLA for Licensure for Fewer Than All of the Reference
Product?s Licensed Conditions of Use ...................................................................................... 4
2. Submission of a Supplement to a 351(k) BLA Seeking Licensure of a Biosimilar or
Interchangeable Biosimilar for an Additional Condition of Use Previously Licensed for the
Reference Product ..................................................................................................................... 5
B. Development of Draft Labeling for a Proposed Biosimilar or Interchangeable Product for
Fewer Than All of the Reference Product?s Licensed Conditions of Use ................................. 5
1. Content of Draft Labeling ......................................................................................................... 5
2. Information to Support Draft Labeling for a Biosimilar or Interchangeable Product for
Fewer Than All of the Reference Product?s Licensed Conditions of Use ................................. 6
C. Timing Considerations for Submission of a 351(k) BLA or Supplement to a 351(k) BLA ..... 6
1. Targeted Timelines for Review.................................................................................................. 7
2. Unexpired Exclusivity................................................................................................................ 8
3. Circumstances Other Than Exclusivity, Including Patents ....................................................... 8
Contains Nonbinding Recommendations
Draft?Not for Implementation
1 Biosimilars and Interchangeable Biosimilars: Licensure for Fewer
2 Than All Conditions of Use for Which the Reference Product Has
3 Been Licensed
4 Guidance for Industry1
5
6
7 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
8 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
9 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
10 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
11 for this guidance as listed on the title page.
12
13
14
15 I. INTRODUCTION
16
17 This guidance provides recommendations to applicants seeking licensure under section 351(k) of
18 the Public Health Service (PHS) Act of a proposed biosimilar or proposed interchangeable
19 biosimilar2
for fewer than all of the reference product?s licensed conditions of use. This
20 guidance also provides recommendations on the submission of a supplement to a licensed 351(k)
21 biologics license application (BLA) seeking to add a condition of use that previously has been
22 licensed3
for the reference product to the labeling4
of a licensed biosimilar or interchangeable
23 product, including considerations related to the timing of such submissions.
24
25 This guidance includes recommendations regarding the following specific issues:
26
27 ? Submission of an application seeking licensure of a proposed biosimilar or proposed
28 interchangeable biosimilar for fewer than all of the reference product?s licensed conditions of
29 use.
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). 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,
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).
Biosimilarity, interchangeability, and related issues are discussed in more detail in section II of this draft guidance.
3
As stated in FDA?s guidance for industry Considerations in Demonstrating Interchangeability With a Reference
Product (May 2019), FDA expects that applicants seeking to demonstrate interchangeability will submit data and
information to support a showing that the proposed interchangeable product can be expected to produce the same
clinical result as the reference product in all of the reference product?s licensed conditions of use. We update
guidances periodically. For the most recent version of a guidance, check the FDA Drugs guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 4
Unless otherwise specified, the terms biosimilar product labeling and labeling as used in this guidance address
only the prescribing information as described in 21 CFR 201.56 and 201.57.
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Contains Nonbinding Recommendations
Draft?Not for Implementation
30 ? Development of proposed labeling when the applicant seeks licensure of a proposed
31 biosimilar or proposed interchangeable product for fewer than all of the reference product?s
32 licensed conditions of use.
33 ? Submission of a supplement to an application for a biosimilar or interchangeable biosimilar
34 to seek licensure for a condition of use previously licensed for the reference product. This
35 may occur, for example, when (1) the biosimilar or interchangeable product was initially
36 licensed for fewer than all of the reference product?s licensed conditions of use, or (2) the
37 reference product is licensed for a new condition of use after licensure of the biosimilar or
38 interchangeable product.
39 ? Timing for the submission of a 351(k) BLA or supplement to a licensed 351(k) BLA
40 described above with the goal of obtaining licensure of a condition of use for a biosimilar or
41 interchangeable product as soon as possible after the expiration of any relevant exclusivity or
42 patents.
43
44 This guidance is one in a series of guidances that FDA is developing to implement the Biologics
45 Price Competition and Innovation Act of 2009 (BPCI Act) and includes references to
46 information from other FDA guidances, where appropriate.
47
48 In general, FDA?s guidance documents do not establish legally enforceable responsibilities.
49 Instead, guidances describe the Agency?s current thinking on a topic and should be viewed only
50 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
51 the word should in Agency guidances means that something is suggested or recommended, but
52 not required.
53
54
55 II. BACKGROUND
56
57 A. The Biosimilar Pathway
58
59 Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI Act, sets forth the
60 requirements for the licensure of a biosimilar or interchangeable biosimilar. Section 351(i)
61 defines biosimilarity to mean ?that the biological product is highly similar to the reference
62 product notwithstanding minor differences in clinically inactive components? and that ?there are
63 no clinically meaningful differences between the biological product and the reference product in
64 terms of the safety, purity, and potency of the product? (section 351(i)(2) of the PHS Act). A
65 BLA submitted under section 351(k) (a ?351(k) BLA?) must contain, among other things,
66 information demonstrating that the biological product is biosimilar to a reference product based
67 upon data derived from analytical studies, animal studies,5
and a clinical study or studies, unless
68 FDA determines, in its discretion, that certain studies are unnecessary in a 351(k) BLA (see
69 section 351(k)(2) of the PHS Act).
70
5
We support the principles of the ?3Rs,? to reduce, refine, and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency
to an animal test method.
2
Contains Nonbinding Recommendations
Draft?Not for Implementation
71 To meet the standard for ?interchangeability,? an applicant must provide sufficient information
72 to demonstrate biosimilarity to the reference product and also to demonstrate that the biological
73 product can be expected to produce the same clinical result as the reference product in any given
74 patient and, if the biological product is administered more than once to an individual, the risk in
75 terms of safety or diminished efficacy of alternating or switching between the use of the
76 biological product and the reference product is not greater than the risk of using the reference
77 product without such alternation or switch (see section 351(k)(4) of the PHS Act).
78 Interchangeable biosimilars may be substituted for the reference product without the intervention
79 of the prescribing healthcare provider (see section 351(i)(3) of the PHS Act).
80
81 B. Licensure of a Biosimilar or Interchangeable Biosimilar for Fewer Than All of the
82 Reference Product?s Licensed Conditions of Use
83
84 A biosimilar or interchangeable biosimilar may be licensed only for conditions of use that have
85 been previously licensed for the reference product.6
An applicant generally may obtain licensure
86 of a biosimilar or interchangeable for fewer than all of the conditions of use for which the
87 reference product is licensed.7
However, FDA recommends that an applicant seeking licensure
88 for a proposed interchangeable product seek licensure for all of the reference product?s licensed
89 conditions of use when possible.8
90
91 A variety of circumstances may lead an applicant to seek licensure of a proposed biosimilar or
92 proposed interchangeable product for fewer than all of the conditions of use for which the
93 reference product is licensed. Examples of these circumstances are described below.
94
95 Orphan-drug Exclusivity
96
97 The reference product may be licensed for one or more indications that are protected by orphan98 drug exclusivity. In such cases, until the applicable exclusivity expires, FDA will not be able to
99 license a biosimilar or interchangeable product for the protected indications. However, assuming
100 that the requirements for licensure are met, FDA may be able to license a biosimilar or
101 interchangeable product for one or more indications of the reference product that are not
102 protected by orphan-drug exclusivity. In such circumstances, an applicant may choose to seek
103 licensure of a biosimilar or interchangeable product for such indications.
104
105 After the applicable orphan-drug exclusivity expires, the applicant may, in a supplement to the
106 licensed 351(k) BLA, seek licensure of the biosimilar or interchangeable biosimilar for a
6
Section 351(k)(2)(A)(i)(III) of the PHS Act.
7 Notably, section 351(k)(4)(A) of the PHS Act provides, among other things, that an application for an
interchangeable product must include information sufficient to show that the proposed interchangeable product ?can
be expected to produce the same clinical result as the reference product in any given patient.? FDA expects that
applicants seeking to demonstrate interchangeability will submit data and information to support a showing that the
proposed interchangeable product can be expected to produce the same clinical result as the reference product in all
of the reference product?s licensed conditions of use. Guidance for industry Considerations in Demonstrating
Interchangeability With a Reference Product (May 2019).
8
Guidance for industry Considerations in Demonstrating Interchangeability With a Reference Product (May 2019).
3
Contains Nonbinding Recommendations
Draft?Not for Implementation
107 previously protected indication, and FDA may license the biosimilar or interchangeable
108 biosimilar for this indication if the requirements for licensure are met.9
109
110 Circumstances Other Than Exclusivity
111
112 ? Patent(s) covering a licensed condition of use of the reference product: An applicant may
113 conclude that a licensed condition of use of the reference product is protected by one or more
114 patent(s). As a result, the applicant may decide not to seek licensure of a proposed biosimilar
115 or proposed interchangeable product for conditions of use that are protected by patent,
116 according to the applicant?s own assessment.
117
118 ? Other reasons: Reasons other than patents or exclusivity may lead an applicant to choose to
119 seek licensure for fewer than all conditions of use for which the reference product is licensed.
120
121 III. RECOMMENDATIONS FOR APPLICANTS SEEKING LICENSURE OF A
122 BIOSIMILAR OR INTERCHANGEABLE BIOSIMILAR FOR FEWER THAN
123 ALL OF THE REFERENCE PRODUCT?S LICENSED CONDITIONS OF USE
124
125 A. Submission of Original 351(k) BLA or Supplement to a 351(k) BLA
126
127 1. Submission of an Original 351(k) BLA for Licensure for Fewer Than All of the
128 Reference Product?s Licensed Conditions of Use
129
130 As part of an original 351(k) BLA, an applicant is expected to submit draft labeling that includes
131 the conditions of use for which the applicant is seeking licensure of the proposed biosimilar or
132 proposed interchangeable product.10, 11 Additional considerations regarding draft labeling are
133 described in section III.B in this guidance. Applicants may contact the appropriate review
134 division in FDA for more information about submitting a 351(k) BLA for licensure of a
135 proposed biosimilar or proposed interchangeable biosimilar for fewer than all of the reference
136 product?s licensed conditions of use.
137
9
Similarly, as provided by section 351(m) of the PHS Act, an additional six-month period of exclusivity will attach
to certain applicable periods of exclusivity if the sponsor conducts pediatric studies that meet the requirements for
pediatric exclusivity pursuant to section 505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). As with
orphan-drug exclusivity, during the applicable period of pediatric exclusivity FDA may be able to license a
biosimilar or interchangeable product for one or more indications of the reference product that are not protected by
such exclusivity, and FDA may license the biosimilar or interchangeable biosimilar for a previously protected
indication after the applicable pediatric exclusivity expires.
10 FDA has issued draft guidance regarding the submission of data and information to support approval of a
proposed biosimilar or interchangeable product for an indication for which the reference product has unexpired
exclusivity. See Q.I.24 in the draft guidance for industry New and Revised Draft Q&As on Biosimilar Development
and the BPCI Act (Revision 2) (December 2018). When finalized, this guidance will represent FDA?s current
thinking on this topic.
11 See section 351(k)(2)(A)(i)(III) of the PHS Act, which requires that a 351(k) application include information
demonstrating that the condition or conditions of use prescribed, recommended, or suggested in the labeling
proposed for the biological product have been previously approved for the reference product.
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138 2. Submission of a Supplement to a 351(k) BLA Seeking Licensure of a Biosimilar or
139 Interchangeable Biosimilar for an Additional Condition of Use Previously Licensed
140 for the Reference Product
141
142 The holder of a licensed 351(k) BLA may, in a supplement to the 351(k) BLA, seek licensure of
143 its biosimilar or interchangeable biosimilar for an additional condition of use that has been
144 previously licensed for the reference product and for which the applicant did not originally seek
145 licensure. A 351(k) BLA holder seeking licensure for an additional condition of use must submit
146 a supplement in accordance with 21 CFR 601.12 seeking licensure of the proposed change. See
147 section III.C.
148
149 A supplement to a 351(k) BLA seeking licensure of a biosimilar or interchangeable biosimilar
150 for an additional condition of use should contain all the data and information needed to support
151 licensure of the biosimilar or interchangeable biosimilar for the proposed condition of use, which
152 may include reference to data and information previously submitted to the 351(k) BLA with
153 appropriate scientific justification. Applicants may contact the appropriate clinical review
154 division at FDA for more information about licensure of a biosimilar or interchangeable
155 biosimilar in such circumstances.
156
157 B. Development of Draft Labeling for a Proposed Biosimilar or Interchangeable
158 Product for Fewer Than All of the Reference Product?s Licensed Conditions of Use
159 FDA?s guidance for industry Labeling for Biosimilar Products (?Biosimilar Labeling
160 Guidance?), provides general recommendations on the development of draft labeling for
161 proposed biosimilar products for submission in a 351(k) BLA.12 In the Biosimilar Labeling
162 Guidance, FDA recommends that labeling for a biosimilar product incorporate relevant data and
163 information from the reference product labeling, with appropriate modifications. The Biosimilar
164 Labeling Guidance also explains that determining which data and information from the reference
165 product labeling should be incorporated into the proposed labeling for a biosimilar will depend
166 on whether the applicant is seeking licensure for all?or fewer than all?of the conditions of use
167 licensed for the reference product.
168
169 1. Content of Draft Labeling
170
171 The applicant should develop draft labeling for the proposed biosimilar or proposed
172 interchangeable biosimilar that includes information from the reference product labeling that is
173 relevant to the proposed conditions of use for the proposed biosimilar or interchangeable, with
174 appropriate modifications. In preparing such draft labeling, the applicant should carefully
175 scrutinize the content of all sections of the labeling to ensure that relevant information is
12 See guidance for industry Labeling for Biosimilar Products (July 2018), which states that it does not provide
specific labeling recommendations for interchangeable products and that any specific recommendations for
interchangeable products will be provided in future guidance.
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176 included, based on the proposed conditions of use for the proposed biosimilar or interchangeable
177 product.13
178
179 FDA will evaluate the labeling to determine whether it complies with applicable requirements.14
180 For example, the labeling must summarize the essential scientific information needed for the safe
181 and effective use of the product.15 FDA regulations also require that prescription drug labeling
182 contain:
183
184 ?adequate information ? including indications, effects, dosages, routes, methods,
185 and frequency and duration of administration and any relevant warnings, hazards,
186 contraindications, side effects, and precautions, under which practitioners licensed
187 by law to administer the drug can use the drug safely and for the purposes for
188 which it is intended ??16
189
190 2. Information to Support Draft Labeling for a Biosimilar or Interchangeable Product
191 for Fewer Than All of the Reference Product?s Licensed Conditions of Use
192
193 In general, FDA does not expect an applicant to submit a justification for the applicant?s decision
194 not to seek licensure of a biosimilar for all of the reference product?s licensed conditions of use.
195 FDA does not consider the applicability of patents to a proposed biosimilar product (e.g., the
196 validity or enforceability of patents or potential infringement) in its review of a 351(k) BLA or
197 supplement to a 351(k) BLA.17 An applicant seeking licensure of a biosimilar or interchangeable
198 biosimilar for fewer than all of the reference product?s licensed conditions of use may, in a
199 351(k) BLA or a supplement to a 351(k) BLA, submit information that is intended to inform
200 FDA?s review of the draft labeling. For example, an applicant may submit a justification as to
201 why, in the applicant?s view, the draft labeling meets the requirements for approval, considering
202 the conditions of use for which the applicant is seeking licensure.
203
204 C. Timing Considerations for Submission of a 351(k) BLA or Supplement to a 351(k)
205 BLA
206
207 The recommendations in this section are intended to facilitate submission of a 351(k) BLA or
208 supplement to a licensed 351(k) BLA with the goal of obtaining licensure of a biosimilar or
209 interchangeable biosimilar soon after expiration of any relevant exclusivity or expiration of a
13 For example, as noted in the guidance for industry Labeling for Biosimilar Products (July 2018), ?in certain
circumstances it may be necessary to include information in the biosimilar product labeling relating to an
indication(s) for which the biosimilar product is not licensed, in order to help ensure safe use ?? Additionally,
although biosimilar labeling need not be identical to reference product labeling, deviations should be carefully
considered to ensure that the condition or conditions of use prescribed, recommended, or suggested in the draft
labeling for the proposed biosimilar product have been previously approved for the reference product (see section
351(k)(2)(A)(i)(III) of the PHS Act).
14 See, e.g., 21 CFR 201.56 and 21 CFR 201.57.
15 See 21 CFR 201.100 and 201.56(a)(1).
16 See 21 CFR 201.100(d)(1) (emphasis added).
17 For more information about the exchange of confidential information for purposes of determining whether a claim
of patent infringement could reasonably be asserted against a 351(k) applicant, refer to section 351(l) of the PHS Act
(42 U.S.C. 262(l)).
6
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210 patent that, in the 351(k) applicant?s assessment, protects a licensed condition of use of the
211 reference product. These recommendations also are applicable to a supplement to a licensed
212 351(k) BLA that seeks licensure of a biosimilar or interchangeable biosimilar for an additional
213 condition of use for which the applicant did not originally seek licensure but that has since been
214 licensed for the reference product.
215
216 1. Targeted Timelines for Review
217
218
219
220
Original 351(k) BLA
As described in the Biosimilar User Fee Act (BsUFA) II Goals Letter, FDA is committed to
reviewing and acting on original 351(k) BLAs within 10 months of the 60-day filing date.18
221
222
223
224
Supplements to a Licensed 351(k) BLA
In the BsUFA II Goals Letter, FDA also committed to reviewing and acting on original 351(k)
BLA supplements with clinical data within 10 months of receipt.19 In light of the anticipated
225 FDA review burden (among other considerations), FDA anticipates that it will review and act on
226 many supplements seeking licensure for additional conditions of use for a licensed biosimilar or
227 interchangeable product before the BsUFA goal date. To the extent practicable, FDA intends
228 that a supplement to a licensed 351(k) BLA seeking licensure of the biosimilar or
229 interchangeable product for an additional condition of use that has been previously licensed for
230 the reference product will be reviewed and acted upon in a 6-month timeframe, without regard to
231 whether the biosimilar or interchangeable product was initially licensed for fewer than all of the
232 reference product?s licensed conditions of use or the reference product is licensed for a new
233 condition of use after licensure of the biosimilar or interchangeable product.
234
235 FDA recognizes that targeting a 6-month timeline for such supplements may surpass, in many
236 cases, the performance goal commitment FDA made in the BsUFA II Goals Letter. Supplements
237 seeking licensure for additional conditions of use for a licensed biosimilar or interchangeable
238 product likely will include clinical data or reference clinical data submitted previously to the
239 351(k) BLA. As noted, the BsUFA II Goals Letter describes a 10-month goal date for original
240 351(k) BLA supplements with clinical data. However, at this time, FDA believes that a review
241 timeframe of 6 months will generally be appropriate for a supplement to a licensed 351(k) BLA
242 seeking licensure of the biosimilar or interchangeable product for an additional condition of use
243 that has been previously licensed for the reference product, assuming the supplement does not
244 raise novel review issues. Among other considerations, this is based on the anticipated FDA
245 review burden associated with these types of supplements. FDA intends to notify applicants in
246 an acknowledgement letter if it believes that the 10-month review timeline described in the
247 BsUFA II Goals Letter is more appropriate for any such supplement.
248
249
18 See Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018
through 2022 (?BsUFA II Goals Letter?) at https://www.fda.gov/media/100573/download. 19 See BsUFA II Goals Letter.
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250 2. Unexpired Exclusivity
251
252
253
The Agency cannot license a biosimilar or interchangeable product for an indication protected by
orphan-drug exclusivity or pediatric exclusivity until the expiration of that exclusivity.20 If an
254 applicant?s proposed labeling includes conditions of use that are protected by unexpired orphan255
256
drug exclusivity or unexpired pediatric exclusivity, the Agency may communicate this issue to
the applicant in the Day 74 letter.21 In these circumstances, an applicant may seek to time the
257 submission of a 351(k) BLA or supplement to a 351(k) BLA with the goal of obtaining licensure
258 after a specific date, such as the expiration of orphan-drug or pediatric exclusivity.
259
260 3. Circumstances Other Than Exclusivity, Including Patents
261
262 As described above, an applicant may choose to seek licensure of a proposed biosimilar or
263 interchangeable biosimilar for fewer than all of the reference product?s licensed conditions of use
264 based on an assessment by the applicant that one or more of the reference product?s licensed
265 conditions of use is protected by patent. In these circumstances, an applicant may seek to time
266 the submission of a 351(k) BLA or supplement to a 351(k) BLA with the goal of obtaining
267 licensure after a specific date, such as the expiration of a patent. Other nonpatent reasons may
268 also lead an applicant to take this approach.
269
270 In contrast to orphan-drug and pediatric exclusivity, the BPCI Act does not limit FDA?s ability to
271 license a 351(k) BLA or a supplement to a 351(k) BLA where a biosimilar seeks licensure for a
272 condition of use which may be subject to one or more patents. FDA may therefore license the
273 product for such condition of use if FDA determines that the requirements for licensure have
274 been met.
275
276
277
Applicants should be aware that FDA may review and act on (i.e., license or issue a complete
response letter to)22 a 351(k) BLA or supplement to a 351(k) BLA before any applicable BsUFA
278 goal date or 6-month targeted review timeline. If an applicant does not want FDA to take action
279 on a 351(k) BLA or supplement to a 351(k) BLA before a specified date, the applicant should
280 request that the Agency refrain from acting on the BLA or supplement before the specified date,
281 so long as that date falls on or before the applicable BsUFA goal date.
282
283 To request that FDA not take action on a 351(k) BLA or supplement to a 351(k) BLA before a
284 specified date, the applicant should include the following language on the cover letter of their
285 BLA or supplement, in bold typeface and prominently placed above the body of the cover letter:
286
287
288
351(k) BLA action timing request: [Applicant Name] requests that FDA not
take action on this [application/supplement] before [specified date].
289
290 If the applicant requests that FDA refrain from taking action on the 351(k) BLA or a supplement
291 to a 351(k) BLA until a specified date that is on or before any applicable BsUFA goal date, the
20 See section 527 of the FD&C Act; section 351(m) of the PHS Act; 21 CFR 316.31. 21 See BsUFA II Goals Letter, p. 10. 22 See BsUFA II Goals Letter, p. 32 (defining ?review and act on? to mean ?the issuance of a complete action letter
after complete review of a filed complete application?).
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292 Agency intends to honor the applicant?s request, where appropriate. Applicants should take
293 BsUFA goal dates into consideration before making such requests. If the requested date extends
294 beyond any applicable BsUFA goal date, the Agency does not intend to honor the applicant?s
295 request.
296
297 Upon receipt of the 351(k) BLA or supplement to a 351(k) BLA containing a request not to act
298 before any applicable BsUFA goal date (or another specified date prior to a BsUFA goal date),
299 FDA int
