Implementation of the 

“Deemed to be a License” Provision of 

the Biologics Price Competition and 

Innovation Act of 2009

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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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 within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (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) Janice Weiner at 301-796-3601 or 

(CBER) Office of Communication, Outreach and Development at 1-800-835-4709 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 2016

Procedural
Implementation of the 

“Deemed to be a License” Provision of 

the Biologics Price Competition and 

Innovation Act of 2009

Guidance for Industry

Additional copies are available from:

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 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida

nces/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

March 2016

Procedural
Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

A. BPCI Act................................................................................................................ 2

B. Transition Period for Certain Biological Products............................................ 4

III. IMPLEMENTATION OF THE “DEEMED TO BE A LICENSE” PROVISION .... 4

A. FDA’s Interpretation of Section 7002(e) of the BPCI Act................................. 4

B. Recommendations for Sponsors of Proposed Protein Products Intended for 

Submission in an Application Under Section 505 of the FD&C Act................ 7

1. “Stand-Alone” New Drug Applications ..................................................... 7

2. 505(b)(2) Applications................................................................................ 8
Contains Nonbinding Recommendations

Draft — Not for Implementation

1

1 Implementation of the “Deemed to be a License” Provision of the

2 Biologics Price Competition and Innovation Act of 2009

3

Guidance for Industry1 4

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 

9 and is not binding on FDA or the public. You can use an alternative approach if it satisfies the 

10 requirements of the applicable statutes and regulations. To discuss an alternative approach, 

11 contact the FDA staff responsible for this guidance as listed on the title page. 

12

13

14

15 I. INTRODUCTION

16

17 This guidance describes FDA’s approach to implementation of the provision of the Biologics 

18 Price Competition and Innovation Act of 2009 (BPCI Act) under which an application for a 

19 biological product approved under section 505 of the Federal Food, Drug, and Cosmetic Act 

20 (FD&C Act) (21 U.S.C. 355) on or before March 23, 2020, will be deemed to be a license for the 

21 biological product under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) 

22 on March 23, 2020. Specifically, this guidance describes FDA’s interpretation of the “deemed to 

23 be a license” provision in section 7002(e) of the BPCI Act for biological products that have been 

24 or will be approved under section 505 of the FD&C Act on or before March 23, 2020. This 

25 guidance also provides recommendations to sponsors of proposed protein products intended for 

26 submission in an application that may not receive final approval under section 505 of the FD&C 

27 Act on or before March 23, 2020, to facilitate alignment of product development plans with 

28 FDA’s interpretation of section 7002(e) of the BPCI Act.

29

30 Although the majority of therapeutic biological products have been licensed under section 351 of 

31 the PHS Act, some protein products historically have been approved under section 505 of the 

32 FD&C Act (see the Appendix to this guidance for examples of such products). On March 23, 

33 2010, the BPCI Act was enacted as part of the Patient Protection and Affordable Care Act 

34 (Public Law 111-148). The BPCI Act changed the statutory authority under which certain 

 1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 

Biologics Evaluation and Research (CBER) at the Food and Drug Administration.

FDA’s guidances for industry are available on the FDA Drugs guidance Web page at 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update 

guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs 

guidance Web page. 
Contains Nonbinding Recommendations

Draft — Not for Implementation

2

protein products will be regulated by amending the definition of a “biological product”2 35 in 

36 section 351(i) of the PHS Act to include a “protein (except any chemically synthesized 

polypeptide).”3 37

38

39 The BPCI Act requires that a marketing application for a “biological product” must be submitted 

40 under section 351 of the PHS Act; this requirement is subject to certain exceptions during a 10-

41 year transition period ending on March 23, 2020 (see section 7002(e)(1)-(3) and (e)(5) of the 

42 BPCI Act and section II of this guidance). On March 23, 2020, an approved application for a 

43 biological product under section 505 of the FD&C Act shall be deemed to be a license for the

44 biological product under section 351 of the PHS Act (see section 7002(e)(4) of the BPCI Act). 

45 This guidance sets forth FDA’s current interpretation of section 7002(e) of the BPCI Act.

46

47 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 

48 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 

49 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 

50 the word should in Agency guidances means that something is suggested or recommended, but 

51 not required. 

52

53 II. BACKGROUND

54

55 A. BPCI Act

56

57 The BPCI Act amended the PHS Act and other statutes to create an abbreviated licensure 

58 pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or 

59 interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 

60 7003 of the BPCI Act). The objectives of the BPCI Act are conceptually similar to those of the 

61 Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 

62 (commonly referred to as the “Hatch-Waxman Act”), which established abbreviated pathways 

63 for the approval of drug products under section 505(b)(2) and 505(j) of the FD&C Act. The 

64 implementation of an abbreviated licensure pathway for biological products can present 

65 challenges given the scientific and technical complexities that may be associated with the larger 

 2 As amended by the BPCI Act, a “biological product” is defined, in relevant part, as “a virus, therapeutic serum, 

toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically 

synthesized polypeptide), or analogous product . . . applicable to the prevention, treatment, or cure of a disease or 

condition of human beings” (see section 351(i) of the PHS Act; see also 21 CFR 600.3(h)). 

3 FDA has interpreted the statutory terms “protein” and “chemically synthesized polypeptide” to implement the 

amended definition of “biological product.” As explained in FDA’s guidance for industry Biosimilars: Questions 

and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (Biosimilars 

Q&A Guidance), the term “protein” means any alpha amino acid polymer with a specific defined sequence that is 

greater than 40 amino acids in size. The term “chemically synthesized polypeptide” means any alpha amino acid 

polymer that (1) is made entirely by chemical synthesis and (2) is less than 100 amino acids in size. A “chemically 

synthesized polypeptide,” as defined, is not a “biological product” and will be regulated as a drug under the FD&C 

Act unless the polypeptide otherwise meets the statutory definition of a “biological product” (see Q&A II.1 in the 

Biosimilars Q&A Guidance).
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66 and typically more complex structure of biological products, as well as the processes by which 

67 such products are manufactured. Most biological products are produced in a living system such 

68 as a microorganism, or plant or animal cells, whereas small molecule drugs are typically 

69 manufactured through chemical synthesis.

70

71 Section 351(k) of the PHS Act, added by the BPCI Act, sets forth, among other things, the 

72 requirements for an application for a proposed biosimilar product and an application or a 

73 supplement for a proposed interchangeable product. Section 351(i) defines “biosimilarity” to 

74 mean “that the biological product is highly similar to the reference product notwithstanding 

75 minor differences in clinically inactive components” and that “there are no clinically meaningful 

76 differences between the biological product and the reference product in terms of the safety, 

77 purity, and potency of the product” (section 351(i)(2) of the PHS Act). A 351(k) application 

78 must contain, among other things, information demonstrating that the biological product is 

79 biosimilar to a reference product based upon data derived from analytical studies, animal studies,

80 and a clinical study or studies, unless FDA determines, in its discretion, that certain studies are 

81 unnecessary in a 351(k) application (see section 351(k)(2) of the PHS Act). To meet the 

82 additional standard of “interchangeability,” an applicant must provide sufficient information to 

83 demonstrate biosimilarity, and also to demonstrate that the biological product can be expected to 

84 produce the same clinical result as the reference product in any given patient and, if the 

85 biological product is administered more than once to an individual, the risk in terms of safety or 

86 diminished efficacy of alternating or switching between the use of the biological product and the 

87 reference product is not greater than the risk of using the reference product without such 

88 alternation or switch (see section 351(k)(4) of the PHS Act). Interchangeable products may be 

89 substituted for the reference product without the intervention of the prescribing health care 

90 provider (see section 351(i)(3) of the PHS Act).

91

92 The BPCI Act also includes, among other provisions: 

93

94 • A 12-year exclusivity period from the date of first licensure of the reference product, 

95 during which approval of a 351(k) application referencing that product may not be made 

96 effective (see section 351(k)(7) of the PHS Act)

97

98 • A 4-year exclusivity period from the date of first licensure of the reference product, 

99 during which a 351(k) application referencing that product may not be submitted (see 

100 section 351(k)(7) of the PHS Act)

101

102 • An exclusivity period for the first biological product determined to be interchangeable 

103 with the reference product for any condition of use, during which a second or subsequent 

104 biological product may not be determined interchangeable with that reference product 

105 (see section 351(k)(6) of the PHS Act)

106

107 • Procedures for identifying and resolving patent disputes involving applications submitted 

108 under section 351(k) of the PHS Act (see section 351(l) of the PHS Act)

109
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110 B. Transition Period for Certain Biological Products

111

112 Section 7002(e) of the BPCI Act provides that a marketing application for a “biological product” 

113 must be submitted under section 351 of the PHS Act, subject to the following exception during a 

114 transition period ending on March 23, 2020:

115

116 • An application for a biological product may be submitted under section 505 of the FD&C 

Act not later than March 23, 2020, if the biological product is in a product class4 117 for 

118 which a biological product in such product class was approved under section 505 of the 

119 FD&C Act not later than March 23, 2010.

120

121 -- However, an application for a biological product may not be submitted under 

122 section 505 of the FD&C Act if there is another biological product approved 

under section 351(a) of the PHS Act that could be a “reference product”5 123 if such 

124 application were submitted under section 351(k) of the PHS Act.

125

126 An approved application for a biological product under section 505 of the FD&C Act shall be 

127 deemed to be a license for a biological product under section 351 of the PHS Act on March 23, 

128 2020.

129

130 III. IMPLEMENTATION OF THE “DEEMED TO BE A LICENSE” PROVISION

131

132 A. FDA’s Interpretation of Section 7002(e) of the BPCI Act

133

134 Section 7002(e) of the BPCI Act is directed to the requirements for submission of an application 

135 for a biological product during the transition period ending on March 23, 2020. The linchpin of 

136 the transition scheme described in section 7002(e) of the BPCI Act is the “deemed to be a 

137 license” provision in section 7002(e)(4); however, the statute is silent regarding 

implementation.6 138 

 4 FDA has interpreted the statutory term “product class” for purposes of determining whether an application for a 

biological product may be submitted under section 505 of the FD&C Act during the transition period (see Q&A II.2

in the Biosimilars Q&A Guidance).

5 The term “reference product” means the single biological product licensed under section 351(a) of the PHS Act 

against which a biological product is evaluated in an application submitted under section 351(k) (see section 

351(i)(4) of the PHS Act).

6 In other legislation, Congress has described the implications of transitioning applications for drug products from 

one statutory scheme to another and has provided for the process that would be used in effecting the transition (see 

section 107(c) of the Drug Amendments of 1962 (Public Law 87-781) (providing that all NDAs effective on the day 

immediately preceding the date of enactment of the Drug Amendments of 1962 shall be deemed approved as of the 

enactment date, and that the provision for withdrawal of approval of an application for lack of effectiveness 

generally would not apply to such deemed NDAs for a period of two years after the enactment date); see also section 

125 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) (Public Law 105-115) (repealing 

section 507 of the FD&C Act and providing that an application for an antibiotic drug approved under section 507 of 

the FD&C Act on the day before enactment of FDAMA shall, on and after the date of enactment, be considered to 

be an NDA submitted and filed under section 505(b) and approved under section 505(c) or an ANDA filed and 

approved under 505(j))).
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139

140 Section 7002(e)(4) provides:

141

142 An approved application for a biological product under section 505 of the Federal Food, 

143 Drug, and Cosmetic Act (21 U.S.C. 355) shall be deemed to be a license for the 

144 biological product under such section 351 [of the PHS Act] on the date that is 10 years 

145 after the date of enactment of [the BPCI Act].

146

147 FDA interprets this provision to mean that on March 23, 2020, applications for biological 

148 products that have been approved under section 505 of the FD&C Act will no longer exist as 

149 New Drug Applications (NDAs) (or, as applicable, Abbreviated New Drug Applications 

150 (ANDAs)) and will be replaced by approved Biologics License Applications (BLAs) under 

section 351(a) or 351(k) of the PHS Act, as appropriate.

7 151 The “deemed to be a license” 

152 provision takes effect “on the date that is 10 years after the date of enactment of this [BPCI] 

153 Act.” Section 7002(e)(4) of the BPCI Act does not provide a mechanism to transition an 

154 approved application under section 505 to an approved BLA under the PHS Act prior to March 

23, 2020, or after March 23, 2020.8 155 

156

157 Section 7002(e)(4) also is explicitly limited to an approved application under section 505 of the 

158 FD&C Act. FDA interprets this provision to mean that the Agency will not approve any 

159 application under section 505 of the FD&C Act for a biological product subject to the transition 

provisions that is pending or tentatively approved9 160 “on” March 23, 2020, even though section 

161 7002(e)(2) of the BPCI Act expressly permits submission of an application under section 505 of 

the FD&C Act “not later than” March 23, 2020, if certain criteria are met.10 162 Therefore, an 

163 application for a protein product that has been submitted under section 505 of the FD&C Act and 

164 is pending on March 23, 2020, will not be able to be approved. Such an application may, for 

 

7 FDA intends to provide additional guidance regarding its approach for determining whether an approved 

application for a biological product under section 505 of the FD&C Act will be deemed a license for the biological 

product under section 351(a) or 351(k) of the PHS Act, and for handling administrative issues associated with the 

transition (including BLA numbers and user fee questions).

8 Compare section 7002(e)(4) of the BPCI Act with section 125 of FDAMA (providing that an approved application 

for the marketing of an antibiotic drug under section 507 of the FD&C Act “shall, on and after such date of 

enactment, be considered to be an application that was submitted and filed under section 505(b) . . . and approved 

for safety and effectiveness under section 505(c)” (emphasis added)) and FDA’s guidance for industry Repeal of 

Section 507 of the Federal Food, Drug, and Cosmetic Act (“All action letters must use the 505(b) or 505(j) 

templates, even for drugs that originally were submitted under section 507, but are the subject of Agency action on 

or after November 21, 1997.”).

9 Tentative approval means that an NDA or ANDA otherwise meets the requirements for approval under the FD&C 

Act but cannot be approved due to an unexpired period of orphan drug exclusivity, or that a 505(b)(2) application or 

ANDA otherwise meets the requirements for approval under the FD&C Act but cannot be approved until the 

expiration of an applicable period of patent and/or exclusivity protection. A drug product that is granted tentative 

approval is not an approved drug and will not be approved until FDA issues an approval letter after any necessary 

additional review of the NDA or ANDA (see 21 CFR 314.105).

10 See King v. Burwell, 135 S.Ct. 2480, at 2492 (2015) (“The Affordable Care Act contains more than a few 

examples of inartful drafting.”).
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165 example, be withdrawn and resubmitted under section 351(a) or 351(k) of the PHS Act, as 

166 appropriate. We recognize that this interpretation could have a significant impact on 

167 development programs for any proposed protein products intended for submission under section 

168 505 of the FD&C Act that are not able to receive final approval by March 23, 2020, and provide 

169 recommendations to sponsors below. 

170

171 Section 7002(e) of the BPCI Act does not explicitly provide a basis for the Agency to treat 

172 approved NDAs or ANDAs for biological products as both NDAs and BLAs after such 

173 applications are deemed to be BLAs on March 23, 2020. Thus, FDA intends to remove NDAs 

174 (and, as applicable, ANDAs) for biological products from FDA’s Approved Drug Products With 

175 Therapeutic Equivalence Evaluations (the Orange Book) on March 23, 2020, based on the 

176 Agency’s position that these products are no longer “listed drugs” and such NDAs may not be 

177 relied upon by a 505(b)(2) applicant or ANDA applicant for approval. After March 23, 2020, 

178 FDA will not approve any pending or tentatively approved 505(b)(2) application (or ANDA) for 

179 a biological product that relied on an approved NDA that was deemed to be a BLA on March 23, 

180 2020. 

181

182 Moreover, with the exception of orphan drug exclusivity, the exclusivity provisions of the FD&C 

183 Act serve to limit the submission or approval of applications under section 505 of the FD&C 

184 Act, but not under section 351 of the PHS Act. Section 7002(e) of the BPCI Act provides that no 

185 applications for biological products may be submitted under section 505 of the FD&C Act after 

186 March 23, 2020. Under the interpretation described above, the Agency will not approve any 

187 applications for biological products under section 505 of the FD&C Act that are pending or 

188 tentatively approved after March 23, 2020. Accordingly, any unexpired period of exclusivity 

189 associated with an approved NDA for a biological product subject to section 7002(e) of the BPCI 

190 Act (e.g., 5-year exclusivity, 3-year exclusivity, or pediatric exclusivity) would cease to have any 

191 effect, and any patents listed in the Orange Book would no longer be relevant for purposes of 

192 determining the timing of approval of a 505(b)(2) application (or ANDA). However, any 

193 unexpired period of orphan drug exclusivity would continue to apply to the drug for the 

194 protected use after March 23, 2020, because orphan drug exclusivity can be granted to and can 

195 block the approval of a drug approved under section 505 of the FD&C Act or a biological 

196 product licensed under section 351 of the PHS Act (see section 527 of the FD&C Act (21 U.S.C. 

197 360cc)). Any post-approval requirements or post-approval commitments, including any pediatric 

198 assessments necessary to comply with the Pediatric Research Equity Act (PREA) (Public Law 

199 108-155), also would transfer to the BLA.

200

201 Finally, FDA interprets section 7002(e) of the BPCI Act and section 351(k)(7) of the PHS Act to 

202 mean that an approved application for a biological product under section 505 of the FD&C Act 

203 that will be deemed to be a license for the biological product under section 351(a) of the PHS Act 

204 on March 23, 2020, will not have been “first licensed under subsection (a)” for purposes of 

205 section 351(k)(7) of the PHS Act, and thus will not receive a period of exclusivity under section 
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351(k)(7)(A) and (B) of the PHS Act.11 206 Section 351(k)(7)(A) and (B) of the PHS Act describe a 

207 12-year exclusivity period during which FDA may not approve a 351(k) application and a 4-year 

208 exclusivity period during which an applicant may not submit a 351(k) application that begin on 

209 “the date on which the reference product was first licensed under subsection (a) [referring to 

210 section 351(a) of the PHS Act].” Nothing in the BPCI Act suggests that Congress intended to 

211 grant biological products approved under section 505 of the FD&C Act — some of which were 

212 approved decades ago — a period of exclusivity upon being deemed to have a license under the 

213 PHS Act that would impede biosimilar or interchangeable product competition in several product 

214 classes until the year 2032. Therefore, FDA interprets section 7002(e) of the BPCI Act together 

215 with section 351(k)(7) of the PHS Act such that the phrase “the date on which the reference 

216 product was first licensed under subsection (a)” in section 351(k)(7)(A) and (B) of the PHS Act 

217 does not apply to biological products that will be deemed to have a license under section 351(a) 

218 of the PHS Act on March 23, 2020.

219

220 B. Recommendations for Sponsors of Proposed Protein Products Intended for 

221 Submission in an Application Under Section 505 of the FD&C Act

222

223 Sponsors of development programs for proposed protein products should evaluate whether a 

224 planned submission under section 505 of the FD&C Act would allow adequate time for approval 

225 of the NDA (or, as applicable, ANDA) prior to March 23, 2020, considering, among other 

226 things, whether the submission may require a second cycle of review and, for certain types of 

227 applications, whether unexpired patents or exclusivity may delay final approval. FDA’s 

228 recommendations for sponsors are based on whether a “stand-alone” or abbreviated development 

229 program is planned. 

230

231 1. “Stand-Alone” New Drug Applications

232

233 An application submitted under section 505(b)(1) of the FD&C Act (i.e., a “stand-alone” NDA) 

234 contains full reports of investigations of safety and effectiveness that were conducted by or for 

235 the applicant or for which the applicant has a right of reference or use. Sponsors of proposed 

236 protein products intended for submission in an NDA under section 505(b)(1) of the FD&C Act 

237 should consider submitting an application under section 351(a) of the PHS Act. Sponsors can

238 contact the relevant review division within the Office of New Drugs in FDA’s CDER with any 

questions about a BLA submission.12 239

 11 The applicability of section 351(k)(7)(A) and (B) of the PHS Act to BLA supplements and subsequent 

applications filed by the same sponsor or manufacturer after March 23, 2020, will be governed by section 

351(k)(7)(C) of the PHS Act. 12 FDA has taken measures to minimize differences in the review and approval of products required to have 

approved BLAs under section 351 of the PHS Act and products required to have approved NDAs under section 

505(b)(1) of the FD&C Act (see section 123(f) of FDAMA). However, for sponsors of proposed protein products

who intend to submit a BLA, it should be noted that a Type II Drug Master File (DMF) for a drug substance, drug 

substance intermediate, or drug product would not be acceptable for a BLA because a license holder is expected to 

have knowledge of and control over the manufacturing process for the biological product for which it has a license. 

FDA is considering a mechanism that, in limited circumstances, would allow holders of approved applications under 

section 505 of the FD&C Act that reference a type II DMF to continue to reference the DMF after the application is 

deemed to be a license under the PHS Act on March 23, 2020. Other types of contract manufacturing arrangements 
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240 2. 505(b)(2) Applications

241

242 A 505(b)(2) application is an NDA that contains full reports of investigations of safety and 

243 effectiveness, where at least some of the information required for approval comes from studies 

244 not conducted by or for the applicant and for which the applicant has not obtained a right of

245 reference or use (e.g., FDA’s finding of safety and/or effectiveness for a listed drug or published 

246 literature). A 505(b)(2) application that seeks to rely on a listed drug must contain adequate data 

247 and information to demonstrate that the proposed product is sufficiently similar to the listed drug 

248 to justify reliance, in part, on FDA’s finding of safety and/or effectiveness for the listed drug. 

249 Any aspects of the proposed product that differ from the listed drug must be supported by 

250 adequate data and information to support the safety and effectiveness of the proposed product. 

251 The timing of approval for a 505(b)(2) application is subject to applicable patent and marketing 

252 exclusivity protections.

253

254 Congress did not provide an approval pathway under the PHS Act that precisely corresponds to 

255 section 505(b)(2) of the FD&C Act. Accordingly, there are additional considerations for 

256 sponsors of proposed protein products intended for submission in a 505(b)(2) application. If a 

257 sponsor anticipates that a planned 505(b)(2) application may not receive final approval on or

258 before March 23, 2020 (e.g., due to the need for a second cycle of review, applicable unexpired 

259 exclusivity or listed patents, or a stay of approval due to patent infringement litigation), the 

260 sponsor should consider the following options:

261

262 • Modifying the development program to support submission of an application under 

263 section 351(a) of the PHS Act (i.e., a “stand-alone” BLA) before or after March 23, 2020. 

264 This may involve, for example, obtaining a right of reference from the application holder 

265 for the listed drug on which the proposed 505(b)(2) application would have relied or 

266 conducting studies with the proposed product to provide the scientific data that otherwise 

would have been relied upon to support approval.13 267

268

269 • Modifying the development program to support submission of a 351(k) BLA for a 

270 proposed biosimilar product or a proposed interchangeable product at such time as there 

271 is a biological product licensed under section 351(a) of the PHS Act that could be a 

272 reference product. 

273

274 Sponsors evaluating whether a proposed product could be submitted under section 351(k) of the 

275 PHS Act should consider whether they would be able to provide information demonstrating that, 

276 among other things, the proposed product:

 

can be considered if the sponsor does not intend to manufacture the product for licensure (see FDA’s guidance for 

industry Cooperative Manufacturing Arrangements for Licensed Biologics). For additional information regarding 

other requirements for BLAs, including potency assays and manufacturing processes, manufacturing facilities, and 

inspection information, please contact the relevant review division. 

13 FDA has issued guidance for industry on Exocrine Pancreatic Insufficiency Drug Products – Submitting NDAs

and is considering how the concepts described in the guidance would apply to proposed pancreatic enzyme products 

submitted under the PHS Act.
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277

278 • is “highly similar” to a single reference product licensed under section 351(a) of the PHS 

279 Act, and that there are “no clinically meaningful differences” between the proposed

280 product and the reference product in terms of safety, purity, and potency

281

282 • has the same route of administration, dosage form, and strength as the reference product

283

284 • utilizes the same mechanism(s) of action as the reference product for the proposed 

285 condition(s) of use (but only to the extent that the mechanism(s) of action are known)

286

287 • seeks licensure for a condition(s) of use (e.g., indication, dosing regimen) previously 

approved for the reference product14 288

289

290 A sponsor of a proposed biological product that could meet the requirements for a proposed 

291 biosimilar and other applicable requirements would be able to submit a 351(k) BLA that cites the 

292 listed drug as its reference product after the NDA for the listed drug is deemed to be a BLA (or 

293 after another product that could be a reference product for the proposed product is licensed under 

294 section 351(a) of the PHS Act). Sponsors that intend to adapt their development programs to 

295 meet the requirements for a submission under section 351(k) of the PHS Act can submit 

296 comparative data with a listed drug that subsequently is deemed to be licensed under section 

351(a) of the PHS Act.

15 297

298

299 Proposed products that are intended to differ in certain respects (e.g., different dosage forms, 

300 routes of administration, strengths, or conditions of use) from a previously approved product 

301 likely would need to be submitted under section 351(a) of the PHS Act and meet applicable 

302 statutory and regulatory requirements for a 351(a) BLA. Such products likely would be unable 

303 to use the 351(k) pathway to abbreviate their development program due to lack of a reference 

304 product or the inability to meet the statutory requirements for a proposed biosimilar product.

305

306 ___________________________________________

307

308

309 A sponsor may contact the relevant review division within the Office of New Drugs in FDA’s 

310 CDER to request advice on a product-specific basis regarding the development of a protein 

311 product intended for submission in an application under the FD&C Act (during the transition 

312 period described in section 7002(e) of the BPCI Act) or under section 351(a) or 351(k) of the 

313 PHS Act, as appropriate.

314

315

 14 See section 351(k) of the PHS Act; see also, generally, FDA’s guidance documents on biosimilar products.

15 Considerations similar to those described for 505(b)(2) applications would apply to any applications submitted 

under section 505(j) during the transition period.
Contains Nonbinding Recommendations

Draft — Not for Implementation

10

316 Appendix 

317

318

319 Examples of Biological Products That Have Been Approved Under the FD&C Act

320

321

chorionic gonadotropin products

desirudin products

follitropin products, urofollitropin products, and menotropins products

hyaluronidase products

imiglucerase products

insulin products, insulin mix products, and insulin analog products 

(e.g., insulin aspart, insulin detemir, insulin glargine, insulin glulisine, and insulin 

lispro products)

mecasermin products

pancrelipase products

pegademase products

pegvisomant products

sacrosidase products

somatropin products

taliglucerase alfa products and velaglucerase alfa products

thyrotropin alfa products

322