Guidance for Industry 
Reference Product Exclusivity for 
Biological Products Filed Under  
 
Section 351(a) of the PHS Act
 
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 electronic comments to http://www.regulations.gov.  Submit written 
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) Sandra Benton at 301-796-2500 or 
(CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 240-402-
7800. 
  
 
 
 
 
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) 
 
August 2014 
Procedural 
 
   
Guidance for Industry 
Reference Product Exclusivity for 
Biological Products Filed Under  
Section 351(a) of the PHS Act 
 
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information, Bldg. 51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Silver Spring, MD 20993  
Phone: 301-796-3400; Fax: 301-847-8714 
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  
ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
(Tel) 800-835-4709 or 301-827-1800 
 
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) 
 
August 2014 
Procedural 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 3 
A.  Licensor, Predecessor in Interest, or Other Related Entity ................................................... 4 
B.  Modification to the Structure of the Biological Product ........................................................ 5 
C.  Result[s] in Change in Safety, Purity, or Potency ................................................................... 6 
IV.  SUGGESTED INFORMATION FOR 351(a) APPLICANTS TO PROVIDE TO 
FDA .................................................................................................................................... 7 
V.  PUBLICATION OF DECISION ..................................................................................... 8 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1
1  Guidance for Industry  
2  Reference Product Exclusivity for Biological Products  
3  Filed Under 351(a) of the PHS Act 
4   
5   
6  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs or the 
7  Agencys) current thinking on this topic.  It does not create or confer any rights for or on any person and 
8  does not operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies 
9  the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, 
10  contact the FDA staff responsible for implementing this guidance.  If you cannot identify the appropriate 
11  FDA staff, call the appropriate number listed on the title page of this guidance.  
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended to assist sponsors who are developing biological products, sponsors of 
17  biologics license applications (BLAs), and other interested parties in providing information that 
18  will help the Agency determine the date of first licensure for a reference product under 
19  351(k)(7)(C) of the Public Health Service Act (PHS Act), as added by the Biologics Price 
20  Competition and Innovation Act of 2009 (BPCI Act).  Under 351(k)(7), licensure of an 
21  application for a biosimilar or interchangeable product under 351(k) of the PHS Act (also known 
22  as a 351(k) application) may not be made effective by FDA until the date that is 12 years after 
23  the date on which the reference product referred to in the 351(k) application was first licensed 
24  under section 351(a) of the PHS Act.  In addition, a 351(k) application may not be submitted to 
25  FDA for review until 4 years after the date of first licensure of the reference product.  This 
26  period of time in which a 351(k) application may not be licensed (or submitted for review) is 
27  known as the reference product exclusivity2 period.  Thus, a decision under 351(k)(7)(C) 
28  regarding the date of first licensure of a reference product submitted under 351(a) is, in effect, a 
29  decision on eligibility for reference product exclusivity and on the date on which such 
30  exclusivity begins to run.   
31   
32  Not every licensure of a biological product under 351(a) is considered a first licensure that 
33  gives rise to its own exclusivity period.  Under the terms of 351(k)(7), the dates of licensure of 
34  applications for certain changes to previously licensed biological products from the same or 
35  certain related sponsors are explicitly not considered the dates of first licensure for purposes of 
36  giving rise to a period of reference product exclusivity.  As discussed further in this guidance, 
37  reference product sponsors generally have superior information about changes to previously 
                                                 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration.   
2 The term exclusivity as applied to a particular product generally refers to a statutory limitation on FDAs ability to 
accept for review or to license or approve certain competing products for a specified period of time.  Exclusivity 
provisions can be found in the Federal Food, Drug, and Cosmetic Act (FD&C Act) at, among others, 505(c)(3)(E), 
505(j)(5)(F), 505A(b) and (c), 527(a), and in the PHS Act at 351(k)(7).  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  licensed  products and corporate relationships to other sponsors that are relevant to a 
39  determination of the date of first licensure under 351(k)(7)(C).  In this guidance, we describe the 
40  types of information that reference product sponsors should provide to facilitate FDAs 
41  determination of the date of first licensure for their products. 
42   
43  FDAs guidance documents, including this guidance, do not establish legally enforceable 
44  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
45  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
46  cited.  The use of the word should in Agency guidances means that something is suggested or 
47  recommended, but not required.  
48   
49  II.  BACKGROUND 
50   
51  The BPCI Act was enacted as part of the Patient Protection and Affordable Care Act (Affordable 
52  Care Act) (Public Law 111148) on March 23, 2010.  The BPCI Act amends the PHS Act and 
53  other statutes to create an abbreviated licensure pathway for biological products shown to be 
54  biosimilar to or interchangeable with an FDA-licensed biological reference product (see sections 
55  7001 through 7003 of the Affordable Care Act).  Section 351(k) of the PHS Act (42 U.S.C. 
56  262(k)), added by the BPCI Act, sets forth the requirements for an application for a proposed 
57  biosimilar product and an application or a supplement for a proposed interchangeable product.   
58   
59  Section 351(k)(7) of the PHS Act, entitled Exclusivity for Reference Product, describes 
60  reference product exclusivity, the period of time in which a 351(k) sponsor is not permitted to 
61  submit and FDA is not permitted to license a 351(k) application that references a reference 
62  product, the single biological product licensed under section 351(a) of the PHS Act against 
63  which a biological product is evaluated in a 351(k) application.3  Under this section, exclusivity 
64  for the reference product is described in terms of a prohibition on acceptance or approval of an 
65  application for a biosimilar or interchangeable product for a period of time starting from the date 
66  of first licensure.  Specifically, approval of a 351(k) application may not be made effective until 
67  12 years after the date of first licensure of the reference product, which under the statute 
68  excludes the date of licensure of supplements and certain other applications.4  A 351(k) 
69  application for a biosimilar or interchangeable biological product cannot be submitted for review 
70  until 4 years after the date on which the reference product was first licensed under section 351(a) 
71  of the PHS Act.5  As provided by section 351(m) of the PHS Act, an additional six-month period 
72  of exclusivity (in which a biosimilar or interchangeable biological product cannot be licensed or 
73  accepted for review) will attach to the 12- and 4-year periods, respectively, if the sponsor 
74  conducts pediatric studies that meet the requirements for pediatric exclusivity pursuant to section 
75  505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act).6  Furthermore, a biological 
76  product seeking licensure as biosimilar to or interchangeable with a reference product indicated 
                                                 
3 Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(4) of the PHS Act. 
4 Sections 7002(a)(7)(A) and 7002(a)(7)(C) of the Affordable Care Act, adding sections 351(k)(7)(A) and 
351(k)(7)(C) of the PHS Act. 
5 Section 7002(a)(7)(B) of the Affordable Care Act, adding section 351(k)(7)(B) of the PHS Act. 
6 Section 7002(g) of the Affordable Care Act, adding section 351(m) of the PHS Act.  This period is referred to as 
the pediatric exclusivity period. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
77  for a rare disease or condition and granted 7 years of orphan drug exclusivity under section 
78  527(a) of the FD&C Act, may not be licensed by FDA for the protected orphan indication until 
79  after the expiration of the 7-year orphan drug exclusivity period or the 12-year reference product 
80  exclusivity period granted under section 351(k)(7) of the PHS Act, whichever is later.7 
81   
82  Determining the date of first licensure for a reference product, in turn, determines whether a 
83  particular biological product qualifies for a period of exclusivity under 351(k)(7) of the PHS Act 
84  and the date on which such exclusivity, if any, will expire.  Making this determination can 
85  present unique challenges given the requirements of section 351(k)(7) of the PHS Act.  These are 
86  made more acute because of the scientific and technical complexities that may be associated with 
87  the larger and typically more complex structures of biological products as compared with small 
88  molecule drugs, as well as the processes by which such biological products are made. Therefore, 
89  the 351(a) applicant may provide information to FDA, such as that described in this guidance or 
90  other relevant information, to assist FDA with its analysis of the date of first licensure for a 
91  biological product under section 351(k)(7) of the PHS Act.8 
92   
93  III.  DISCUSSION     
94   
95  A biological product submitted for licensure under section 351(a) of the PHS Act (a 351(a) 
96  application) may be eligible for a period of exclusivity that commences on the date of its 
97  licensure unless its date of licensure is not considered a date of first licensure because it falls 
98  within an exclusion under 351(k)(7)(C).  In most instances, the date of first licensure will be the 
99  initial date the particular product at issue was licensed in the United States.   
100   
101  Under section 351(k)(7)(C) of the PHS Act, however, the date of first licensure does not include 
102  the date of licensure of (and a new period of exclusivity shall not be available for) a biological 
103  product licensed under section 351(a) of the PHS Act if the licensure is for: 
104   
105    a supplement for the biological product that is the reference product; or 
106    a subsequent application filed by the same sponsor or manufacturer of the 
107  biological product (or a licensor, predecessor in interest, or other related 
108  entity) for: 
109    a change (not including a modification to the structure of the 
o
110  biological product) that results in a new indication, route of 
111  administration, dosing schedule, dosage form, delivery system, 
112  delivery device, or strength; or 
113    a modification to the structure of the biological product that does not 
o
114  result in a change in safety, purity, or potency.9 
115   
                                                 
7 Section 7002(h) of the Affordable Care Act. 
8 This guidance document does not include an exhaustive list of information that a sponsor may submit to assist 
FDA in determining the date of first licensure.  FDA recommends that sponsors submit any additional information 
regarding the date of first licensure that they think supports eligibility for exclusivity and include an explanation of 
its relevance.   
9 Section 7002(a)(7)(C) of the Affordable Care Act, adding section 351(k)(7)(C) of the PHS Act. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
116  The exclusions noted above indicate that Congress did not intend for every biological product 
117  licensed under section 351(a) of the PHS Act to be eligible for a separate period of reference 
118  product exclusivity.  Because of these exclusions, for each product licensed under section 351(a) 
119  of the PHS Act that may serve as a reference product for a biosimilar application, FDA must 
120  make a determination regarding the date of first licensure.   
121   
122  Thus, for instance, FDA must determine whether an application is considered a subsequent 
123  application filed by the same sponsor or manufacturer of the biological product (or a licensor, 
124  predecessor in interest, or other related entity).  For such applications, FDA must determine 
125  whether a particular application is for a modification to the structure of a biological product 
126  previously licensed by such an entity.  If FDA concludes that a particular application filed by a 
127  relevant entity includes a modification to the structure of a previously licensed biological 
128  product that was the subject of a 351(a) application filed by the same sponsor or manufacturer, or 
129  its licensor, predecessor in interest, or other related entity, FDA must also determine whether 
130  such a structural modification would result in a change in safety, purity, or potency.   
131   
132  A sponsor may submit the information described in section IV of this guidance document to 
133  assist FDA in determining the date of first licensure for a biological product to determine 
134  whether the product is eligible for its own period of exclusivity or is subject to an exclusion 
135  described in 351(k)(7)(C).  If the sponsor cannot adequately characterize the biological product, 
136  FDA recommends that the sponsor consult FDA for additional guidance.   
137   
138  A.  Licensor, Predecessor in Interest, or Other Related Entity 
139   
140  Section 351(k)(7)(C) of the PHS Act excludes from the date of first licensure the date of 
141  approval of supplements and certain subsequent applications filed by the same sponsor or a 
142  licensor, predecessor in interest, or other entity that is related to the sponsor of a previously 
143  licensed biological product.  The Agency has experience in construing other provisions that 
144  require examination of the relationships between business entities to determine eligibility of a 
145  new drug application for exclusivity.10  For example, in the context of 3-year new drug product 
146  exclusivity, the Agency has included studies conducted or funded by the applicants predecessor 
147  in interest in any assessment of eligibility for exclusivity.  It has construed the term predecessor 
148  in interest to mean an entity (e.g., a corporation) that the sponsor has taken over, merged with, 
149  or purchased, or from which the sponsor has purchased all rights to the drug [reference 
150  product].11  Also, the Agency has construed a predecessor in interest to include an entity which 
151  has granted to the applicant exclusive rights to a new drug application or the data upon which 
152  exclusivity is based, which may include licensors, assignors, and joint venture partners, 
153  depending on the circumstances of the case.12   
154   
                                                 
10 Sections 505(c)(3)(E)(iii) and 505(j)(5)(F)(iii) of the FD&C Act (requiring that a study be conducted or 
sponsored by the applicant to qualify for 3-year new drug product exclusivity).   
11 21 CFR 314.108(a); see also 21 CFR 314.50(j)(4)(iii). 
12 See the final rule entitled Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions 
(patent and exclusivity final rule), published in the Federal Register of October 3, 1994 (59 FR 50338 at 50359 and 
50362).  Sections 21 CFR 314.108(a) and 314.50(j)(4)(iii) also state that the purchase of nonexclusive rights to a 
clinical investigation after it is completed is not sufficient to satisfy this definition of predecessor in interest. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
155  With respect to 351(k)(7)(C), the Agency intends to interpret the term predecessor in interest 
156  as it does in the 3-year new drug product exclusivity context.13  It will consider any entity that 
157  the sponsor has taken over, merged with, or purchased, or that has granted the sponsor exclusive 
158  rights to market the biological product under the 351(a) application, or had exclusive rights to the 
159  data underlying that application to be a predecessor in interest for purposes of the first licensure 
160  provisions at section 351(k)(7)(C) of the PHS Act.   
161   
162  The Agency intends to consider a licensor under the BPCI Act to be any entity that has granted 
163  the sponsor a license to market the biological product, regardless of whether such license is 
164  exclusive.  This term would include, for instance, entities that continue to retain rights to 
165  develop, manufacture, or market the biological product, and/or rights to intellectual property that 
166  covers the biological product.   
167   
168  Although the BPCI Act does not define the term other related entity, the Agency generally will 
169  consider an applicant to be a related entity in this context if (1) either entity owns, controls, or 
170  has the power to own or control the other entity (either directly or through one or more other 
171  entities) or (2) the entities are under common ownership or control.  The Agency also may find 
172  that two parties are related entities for purposes of the BPCI Act if the entities are or were 
173  engaged in certain commercial collaborations relating to the development of the biological 
174  product(s) at issue.14  In analyzing whether the relationship between the parties would result in a 
175  finding that they were other related entities, the Agency expects to consider not only 
176  ownership and control of the investigational new drug application (IND) and the BLA, but also 
177  the level of collaboration between the entities during the development program as a whole.   
178   
179  B.  Modification to the Structure of the Biological Product 
180   
181  The statute specifies that the date of first licensure excludes (and, therefore, a new period of 
182  exclusivity will not run from) the date of approval of an application for a change that results in a 
183  new indication, route of administration, dosing schedule, dosage form, delivery system, delivery 
184  device, or strength unless that change includes a modification to the structure of the biological 
185  product and such modification results in a change in safety, purity, or potency.  It is thus 
186  essential to first determine whether a new product includes a modification to the structure of a 
187  previously licensed product to assess whether the licensure of the new product is a first licensure 
188  that triggers its own period of exclusivity.  
189   
190  Therefore, a sponsor seeking to assist FDA in determining the date of first licensure for a 
191  reference product licensed under 351(a), should describe the structural similarities and 
192  differences between its proposed product and any previously licensed biological product that was 
193  the subject of a 351(a) application filed by the same sponsor or manufacturer (or its licensor, 
194  predecessor in interest, or other related entity).  For protein products, described structural 
195  differences should include, as appropriate, any differences in amino acid sequence, glycosylation 
196  patterns, tertiary structures, post-translational events (including any chemical modifications of 
                                                 
13 Patent and exclusivity final rule (59 FR 50338 at 50362). 
14 This generally would not include service contracts, unless such contracts reflect common ownership or 
development of the product(s) at issue. 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
197  the molecular structure such as pegylation), and infidelity of translation or transcription, among 
198  others.  In determining whether a biological product includes a modification to the structure of a 
199  previously licensed biological product, FDA also will consider the principal structural molecular 
200  features of both products and whether the modified product affects the same molecular target as 
201  the previously licensed product.  If a sponsor employs a cell line modified from that used to 
202  manufacture the previously licensed product (for example, one employing a modified gene 
203  construct) to manufacture a new product, modification of the structure will not simply be 
204  presumed.  Instead, a sponsor seeking to demonstrate that this new product is nevertheless 
205  eligible for its own period of exclusivity should first demonstrate that the product has been 
206  structurally modified. Any demonstration that the structure has been modified should be 
207  followed by a demonstration that the change has resulted in a change in safety, purity, or 
208  potency, as explained in section III.C below. 
209   
210  C.  Result[s] in Change in Safety, Purity, or Potency 
211   
212  Section 351(k)(7)(C)(ii)(II) of the PHS Act excludes from the date of first licensure the dates of 
213  approval of those modifications to the structure of the previously licensed product that do not 
214  result in a change in safety, purity, or potency.15  The determination of whether a structural 
215  modification results in a change in safety, purity, or potency will be made case-by-case and will 
216  generally need to be based on data submitted by the sponsor.  The supporting information 
217  provided should include measurable effects (typically demonstrated in preclinical or clinical 
218  studies and shown by relevant methods such as bioassays) clearly describing how the 
219  modification resulted in a change in safety, purity, or potency compared to the previously 
220  licensed product.  Supporting information can include references to the data and information 
221  submitted in the 351(a) application of the previously licensed product.  Evidence that a change 
222  resulted in a change in safety, purity, or potency may include evidence that the change will result 
223  in a meaningful benefit to public health, such as a therapeutic advantage or other substantial 
224  benefit when compared to the previously licensed biological product.   
225   
226  In cases where FDA determines that a proposed biological product includes a modification to the 
227  structure of a previously licensed biological product, FDA generally will presume that the 
228  modification has resulted in a change to the proposed products safety, purity, or potency if the 
229  sponsor of the proposed product demonstrates that it affects a different molecular target than the 
230  original product.  A molecular target can be any molecule in the body whose activity is modified 
231  by the product, resulting in a desirable therapeutic effect.  Such molecular targets can include 
232  receptors, enzymes, ion channels, structural or membrane transport proteins, nucleic acids, and 
233  pathogens, among others.   
234   
                                                 
15 The standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been 
interpreted to include effectiveness (see 21 CFR 600.3(s) and the guidance for industry Providing Clinical Evidence 
of Effectiveness for Human Drug and Biological Products).  In that guidance, we use the terms safety and 
effectiveness and safety, purity, and potency interchangeably in the discussions pertaining to biosimilar products.  
We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
235  If the modified product affects the same molecular target as the previously licensed product, its 
236  sponsor should provide data to show that the changes in structure result in a change in safety, 
237  purity, or potency of the modified product when compared to the previously licensed product.  If 
238  a sponsor can provide such data, FDA may determine that the date of licensure of the modified 
239  product is the date of first licensure as set forth in section 351(k)(7)(C) of the PHS Act.   
240   
241  If the sponsor does not demonstrate that a modification in the structure results in a change in 
242  safety, purity, or potency compared to the previously licensed product, or that the modified 
243  product affects a different molecular target than the previously licensed product (resulting in a 
244  presumption that there is a change in safety purity or potency), the date of licensure of the 
245  modified product generally would not be the date of first licensure, and that product would 
246  therefore not be eligible for its own period of exclusivity.   
247   
248  Under 351(k)(7)(C)(ii)(I) of the PHS Act, the date of approval of a change to a previously 
249  licensed product from the same sponsor (or a licensor, predecessor in interest, or other related 
250  entity) that does not include a modification to the structure of the sponsors original product but 
251  which results in a new indication, route of administration, dosing schedule, dosage form, 
252  delivery system, delivery device, or strength is excluded from the date of first licensure; and an 
253  application for such a change is not eligible for its own period of exclusivity.  
254   
255  IV.  SUGGESTED INFORMATION FOR 351(a) APPLICANTS TO PROVIDE TO 
256  FDA 
257   
258  FDA recommends that a sponsor include information such as that described in this guidance at 
259  the time the 351(a) application is submitted or, in the case of an already licensed 351(a) 
260  application, as correspondence to the application.16  Alternatively, this information can be 
261  submitted as an amendment to the 351(a) application.  However, the determination of the date of 
262  first licensure and of eligibility for exclusivity may not always be made at the time of licensure, 
263  particularly if the determination presents complicated scientific, legal, or factual issues; if the 
264  information to support such a determination is submitted late in the review cycle; if such 
265  information is incomplete; or if FDA requests additional information to make its determination.  
266   
267  To assist FDA in evaluating the date of first licensure as described in section 351(k)(7)(C) of the 
268  PHS Act, FDA suggests that sponsors provide the following information: 
269   
270  1.  A list of all licensed biological products that are structurally related to the biological 
271  product that is the subject of the 351(a) application being considered.  This list should 
272  include products that share some of the same principal molecular structural features of 
273  the product being considered, but generally can be limited to products that affect the 
                                                 
16 The Agency recommends, however, that any exclusivity request be placed specifically in the electronic common 
technical document (eCTD) Module 1.3.5.3 (the Exclusivity Claim section of Module 1, Administrative 
Information) of the application. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
274  same molecular target.17  Products that target different epitopes of the same molecular 
275  target should be included.  Where specific molecular targets have not been defined, this 
276  list should include products that share the narrowest target that can be characterized.  
277  This may be a pathway, cell type, tissue, or organ system.  If this assessment results in 
278  the conclusion that no product that has the same molecular target or shares some of the 
279  same principal molecular structural features has been licensed, a sponsor should provide 
280  an adequate justification to support the assertion that there are no previously licensed 
281  products that are relevant for purposes of determining the date of first licensure.  
282   
283  2.  Of those licensed biological products identified in item 1 above, a list of those for which 
284  the sponsor or one of its affiliates, including any licensors, predecessors in interest, or 
285  related entities,18 are the current or previous license holder.   
286   
287  3.  Description of the structural differences between the proposed product and any products 
288  identified in item 2 above.  For protein products, this should include, but is not limited to, 
289  changes in amino acid sequence, differences due to post-translational events, infidelity of 
290  translation or transcription, differences in glycosylation patterns or tertiary structure, and 
291  differences in biological activities.19    
292   
293  4.  Evidence of the change in safety, purity, and/or potency between the proposed product 
294  and any products identified in item 2 above.  This should include, but is not limited to, a 
295  description of how the structural differences identified in item 3 above relate to changes 
296  in safety, purity, and/or potency.    
297   
298  Any other information and data that would assist the FDA in making a determination regarding 
299  the date of first licensure for a 351(a) application should also be included. 
300   
301  V.  PUBLICATION OF DECISION 
302   
303  FDA is reviewing options for making information publicly available regarding reference product 
304  exclusivity and dates of first licensure.  Once a method is determined, plans to communicate this 
305  information will be provided on FDAs Web site. 
                                                 
17 See, for example, 21 CFR 316.3(b)(13) and its definition of same drug as it relates to orphan drug products and 
the description of structural differences of large molecule drug products. 
18 In compiling this list, predecessor in interest, licensor, and other related entity should be defined as 
described in section III.A of this guidance. 
19 Biological activities can be an important measure of structural changes. 
  8