Clinical Immunogenicity 
Considerations for Biosimilar 
and Interchangeable Insulin 
Products  
 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 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.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2019 
Biosimilars 
 
   
Clinical Immunogenicity 
Considerations for Biosimilar 
and Interchangeable Insulin 
Products  
 
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  
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 November 2019 
Biosimilars 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DATA EXPECTATIONS FOR PROPOSED BIOSIMILAR AND 
INTERCHANGEABLE INSULIN PRODUCTS ....................................................................... 5 
IV.  CLINICAL EVALUATIONS OF IMMUNOGENICITY ............................................ 7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Clinical Immunogenicity Considerations for Biosimilar  
1 
and Interchangeable Insulin Products 
2 
 
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 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  I.  INTRODUCTION  
15   
16  The purpose of this guidance is to provide recommendations to applicants regarding whether and 
17  when comparative clinical immunogenicity studies may be needed to support licensure of 
18  proposed biosimilar and interchangeable recombinant human insulins, recombinant human 
19  insulin mix products, and recombinant insulin analog products that are intended for the treatment 
20  of patients with Type 1 or Type 2 diabetes mellitus (collectively described as insulin products).  
21  The recommendations in this guidance are applicable only to proposed biosimilar and 
22  interchangeable insulin products seeking licensure under section 351(k) of the Public Health 
23  Service Act (PHS Act) in biologics license applications (BLAs).  
24   
25  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
26  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
27  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
28  the word should in Agency guidances means that something is suggested or recommended, but 
29  not required.  
30   
31  II.  BACKGROUND 
32   
33  A.  The Pathway for Biosimilar and Interchangeable Insulin Products 
34   
35  Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) 
36  requires that on March 23, 2020, an approved application for a biological product under section 
37  505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) will be deemed 
38  to be a license for the biological product under section 351 of the PHS Act (42 U.S.C. 262).  
39  Although the majority of therapeutic biological products have been licensed under section 351 of 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug 
Administration (FDA or the Agency).  We update guidances periodically.  To make sure you have the most recent 
version of a guidance, check the FDA Drugs guidance web page at https://www.fda.gov/drugs/guidance-
compliance-regulatory-information/guidances-drugs.    
 
  1 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
40  the PHS Act, some protein products historically have been approved under section 505 of the 
41  FD&C Act.2   
42   
43  This transition provision affects the insulin products to which this guidance is applicable.  On 
44  March 23, 2020, the approved new drug applications (NDAs) for insulin products will be 
45  deemed to be licenses under section 351(a) of the PHS Act.  Products with deemed BLAs will 
46  then be available to be used as reference products by applicants seeking licensure of proposed 
47  biosimilar and interchangeable insulin products under section 351(k) of the PHS Act.3 
48   
49  Section 351(k) of the PHS Act (42 U.S.C. 262(k)) sets forth the requirements for the licensure of 
50  biosimilar and interchangeable products.  Section 351(i) defines biosimilarity to mean that the 
51  biological product is highly similar to the reference product notwithstanding minor differences in 
52  clinically inactive components (referred to hereafter as highly similar) and that there are no 
53  clinically meaningful differences between the biological product and the reference product in 
54  terms of the safety, purity, and potency of the product (referred to hereafter as no clinically 
55  meaningful differences).4  To be licensed as a biosimilar, an application submitted under section 
56  351(k) must contain, among other things, information demonstrating that the biological product 
57  is biosimilar to a reference product based upon data derived from analytical studies 
58  demonstrating that the proposed biosimilar is highly similar to the reference product, animal 
59  studies, and a clinical study or studies (including the assessment of immunogenicity and 
60  pharmacokinetics (PK) or pharmacodynamics (PD)) (see section 351(k)(2)(A)(i)(I) of the PHS 
61  Act).  FDA has the discretion to determine that an element described in section 
62  351(k)(2)(A)(i)(I) is unnecessary in a 351(k) application (see section 351(k)(2)(A)(ii) of the PHS 
63  Act).   
64   
65  To be licensed as an interchangeable, an applicant must provide sufficient information to 
66  demonstrate biosimilarity to the reference product, and also to demonstrate that the biological 
67  product can be expected to produce the same clinical result as the reference product in any given 
68  patient and, if the biological product is administered more than once to an individual, the risk in 
69  terms of safety or diminished efficacy of alternating or switching between the use of the 
70  biological product and the reference product is not greater than the risk of using the reference 
71  product without such alternation or switch (see section 351(k)(4) of the PHS Act).  The terms 
72  interchangeable or interchangeability mean that the biological product may be substituted 
                                                 
2 The BPCI Act also clarified the statutory authority under which certain protein products will be regulated by 
amending the definition of a biological product in section 351(i) of the PHS Act to include a protein (except any 
chemically synthesized polypeptide) and describing procedures for submission of a marketing application for 
certain biological products.  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).
 
3 Guidance for industry Interpretation of the Deemed to be a License Provision of the Biologics Price 
Competition and Innovation Act of 2009 (December 2018). 
4 Section 351(i)(2) of the PHS Act; see also, guidance for industry Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product (April 2015) for recommendations on demonstrating biosimilarity, including 
considerations for demonstrating that a proposed product is highly similar to its reference product notwithstanding 
minor differences in clinically inactive components and that there are no clinically meaningful differences between 
the two products in terms of safety, purity, and potency.    
 
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
73  for the reference product without the intervention of the health care provider who prescribed the 
74  reference product (see section 351(i)(3) of the PHS Act). 
75   
76  B.  Scientific Considerations for Proposed Biosimilar and Interchangeable Insulin 
77  Products 
78   
79  FDA has approved many insulin products in NDAs submitted pursuant to section 505(b)(1) of 
80  the FD&C Act.  FDA also has approved follow-on insulin products in NDAs submitted 
81  pursuant to the abbreviated approval pathway described in section 505(b)(2) of the FD&C Act.  
82  505(b)(1) and 505(b)(2) NDAs must meet the same statutory requirements regarding safety and 
83  substantial evidence of effectiveness.5  In the past, FDA generally has advised that clinical 
84  studies to evaluate potential risks from immunogenicity associated with proposed insulin 
85  products may be necessary to support NDA approval.   
86   
87  In addition, FDA previously has taken the position that data from a comparative clinical 
88  immunogenicity study would likely be needed to evaluate the potential risk and clinical impact 
89  of immunogenicity of proposed biosimilar and interchangeable insulin products in 351(k) BLAs.  
90  This recommendation was consistent with general principles set forth in guidances for industry 
91  on proposed biosimilar and interchangeable products in 351(k) BLAs generally,6 and 
92  recommendations historically given in the context of applications submitted pursuant to section 
93  505 of the FD&C Act.    
94   
95  In this guidance, FDA describes its updated thinking that, generally, if a comparative analytical 
96  assessment based on state-of-the-art technology supports a demonstration of highly similar for 
97  a proposed biosimilar or interchangeable insulin product, there would be little or no residual 
98  uncertainty regarding immunogenicity; in such instances, the proposed biosimilar or 
99  interchangeable insulin product, like the reference product, would be expected to have minimal 
100  or no risk of clinical impact from immunogenicity.  In such instances, a comparative clinical 
101  immunogenicity study generally would be unnecessary to support a demonstration of 
102  biosimilarity or interchangeability.  For some proposed biosimilar or interchangeable insulin 
103  products, a comparative clinical immunogenicity study may still be needed to address residual 
104  uncertainty regarding immunogenicity.  For example, such a study would be needed to address 
105  uncertainty raised by, among other things, differences in certain impurities or novel excipients, 
106  but that would be a case-by-case scientific determination in the context of individual 
107  applications. 
108   
109  This updated recommendation is based on an extensive multidisciplinary evaluation involving 
110  several considerations, including:   
111   
112    the relatively small, structurally uncomplicated7 and well-characterized nature of insulin 
                                                 
5 See section 505(b)-(d) of the FD&C Act. 
6 See e.g., guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 
(April 2015); guidance for industry Considerations in Demonstrating Interchangeability With a Reference Product 
(May 2019).   
7 Given their relatively small size among biologics and few post-translational modifications, insulin products are 
described herein as structurally uncomplicated. 
  3 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
113  products in comparison to the vast majority of biologics, which generally allows for a 
114  comprehensive analytical evaluation, leaving little or no residual uncertainty regarding 
115  risk of clinical impact from immunogenicity;  
116   
117    extensive experience and literature survey that confirm minimal or no clinical relevance 
118  of immunogenicity with insulin product use; and 
119   
120    scientific thinking on the lack of clinical impact of immunogenicity with insulin product 
121  use, as reflected in: 
122   
123  o  Decades of clinical experience with approved insulin products, including the lack 
124  of a correlation between immunogenicity and safety or effectiveness as reflected 
125  in approved product labeling for insulin products. 
126   
127  o  Public comments received by FDA in response to the May 2019 public meeting, 
128  The Future of Insulin Biosimilars:  Increasing Access and Facilitating the 
129  Efficient Development of Biosimilar and Interchangeable Insulin Products.  FDA 
130  held that public meeting in order to receive input from stakeholders on, among 
131  other things, the development process for biosimilar and interchangeable insulin 
132  products.  FDA carefully considered the presentations given at that meeting and 
133  comments submitted to the docket, many of which asserted that comparative 
134  clinical immunogenicity studies are unnecessary for licensure of biosimilar or 
135  interchangeable insulin products.8  
136   
137  o  Updated recommendations from the European Medicines Agency, which 
138  published a revised guideline in 2015 that no longer recommends a clinical 
139  immunogenicity study to support a biosimilar marketing application.9  
140   
141  o  Published literature, including reports of clinical trial results in adults and 
142  pediatric patients with diabetes and retrospective reviews, which indicated a poor 
143  correlation between immunogenicity in insulin-treated patients and clinical impact 
144  on safety and efficacy and confirmed minimal or no risk of clinical impact from 
145  immunogenicity.10   
                                                 
8 Docket FDA-2019-N-1132, The Future of Insulin Biosimilars:  Increasing Access and Facilitating the Efficient 
Development of Biosimilar and Interchangeable Insulin Products.  Additional comments to the docket discussed 
concerns about immunogenicity when alternating or switching between medications, including comments regarding 
the type and amount of data FDA should expect for licensure of products under section 351(k).  FDA carefully 
considered all relevant comments in developing the recommendations contained in this guidance. 
9 European Medicines Agency, Guideline on nonclinical and clinical development of similar biological medicinal 
products containing recombinant human insulin and insulin analogues. EMEA/CHMP/BMWP/32775/2005_Rev. 1 
(2015)   
10 See, e.g., Richter B and G Neises, 2005, 'Human' insulin versus animal insulin in people with diabetes mellitus, 
Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD003816; Fineberg, SE, et al, 2007, Immunological 
Responses to Exogenous Insulin, Endocr Rev, 28(6):625-652; Thalange N, et al, 2016, Development of Insulin 
Detemir/Insulin Aspart Cross-Reacting Antibodies Following Treatment with Insulin Detemir:  104-week Study in 
Children and Adolescents with Type 1 Diabetes Aged 216 Years, Diabetes Ther 7:713-724; Ilag LL, et al, 2016, 
Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus insulin glargine in patients 
 
  4 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
146   
147  The science and technology of protein manufacturing has advanced considerably over time.  As 
148  described in the draft guidance for industry Development of Therapeutic Protein Biosimilars:  
149  Comparative Analytical Assessment and Other Quality-Related Considerations (May 2019),11 
150  improvements in manufacturing processes, process controls, materials, and product testing, as 
151  well as characterization tests and studies, have led to evolution in the understanding and 
152  extensive characterization of protein products.  This is particularly true of insulin products, 
153  which, in contrast to other biologics, are relatively small, structurally uncomplicated proteins that 
154  are well-understood and well-characterized.12    
155   
156  In addition, decades of experience with the development and wide clinical use of insulin 
157  products has contributed to scientific understanding of insulin products.  There are numerous 
158  new drug applications for insulin products listed in FDAs Approved Drug Products with 
159  Therapeutic Equivalence Evaluations (the Orange Book).  Under the guidance of health care 
160  practitioners, both short- and long-acting insulin products are used by patients with type 1 and 
161  type 2 diabetes, with changes in doses and insulin products over time.  To date, this extensive 
162  clinical experience with approved insulin products has identified no meaningful clinical impact 
163  of immunogenicity on the safety or efficacy of insulin product use.  This scientific 
164  understanding, as well as better purification methods developed over time, has resulted in 
165  diminished concerns about the risk of clinical impacts from immunogenicity for currently 
166  approved insulin products.   
167   
168  Current analytical tools used to evaluate quality attributes for insulin products can support a 
169  comprehensive analytical comparison thorough enough to support a conclusion that a particular 
170  proposed biosimilar insulin product that is highly similar to its reference product generally 
171  would have little or no residual uncertainty regarding immunogenicity and would be expected, 
172  like the reference product, to have minimal or no risk of clinical impact from immunogenicity.  
173  In such cases, a comparative clinical immunogenicity study would generally not be necessary to 
174  support licensure of a proposed biosimilar or interchangeable product. 
175   
176  III.  DATA EXPECTATIONS FOR PROPOSED BIOSIMILAR AND 
177  INTERCHANGEABLE INSULIN PRODUCTS 
178   
179  A comparative clinical immunogenicity study generally would be considered unnecessary to 
                                                 
with type 1 or type 2 diabetes mellitus, Diabetes Obes Metab 18(2):159-168; Home P, et al, 2018, Anti-Insulin 
Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People 
with Diabetes, Diabetes Technol Ther 20(2):160-170.  See also Yamada T, et al, 2018, Biosimilar vs. originator 
insulins:  Systematic review and meta-analysis, Diabetes Obes Metab, 20(7):1787-1792; Heinemann L, 2012, 
Biosimilar insulins, Expert Opin Biol Ther, 12(8):1009-1016; Kuhlmann M and A Schmidt, 2014, Production and 
manufacturing of biosimilar insulins:  implications for patients, physicians, and health care systems, Biosimilars, 
4:45-58; Heinemann L and M Hompesch, 2014, Biosimilar Insulins:  Basic Considerations, J Diabetes Sci Technol, 
8(1):6-13. 
11 This draft guidance, when finalized, will represent FDAs current thinking on this topic.    
12 Regular human insulin is comprised of two non-glycosylated alpha amino acid polymers with a specific, defined 
sequence consisting of amino acid chain subunits with 21 amino acids and 30 amino acids that form a disulfide-
bonded heterodimer, respectively, totaling more than 40 amino acids.  All currently approved insulin analogs differ 
minimally in their amino acid sequence from regular human insulin.   
 
  5 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
180  support a demonstration of biosimilarity in a 351(k) BLA for a proposed insulin product seeking 
181  licensure as a biosimilar or interchangeable if the BLA contains a robust and comprehensive 
182  comparative analytical assessment demonstrating that the proposed insulin product is highly 
183  similar to its proposed reference product with very low residual uncertainty regarding 
184  immunogenicity and the application otherwise meets the standards for licensure under section 
185  351(k) of the PHS Act.13   
186   
187  FDA recommends that a 351(k) BLA for a biosimilar or interchangeable insulin product contain, 
188  among other things: 
189   
190    Adequate chemistry, manufacturing, and control (CMC) information to fulfill product 
191  quality-related requirements described in 21 CFR 601.2, including a validated 
192  manufacturing process,14 and to support an inspection of the facility that is the subject of 
193  the application (i.e., a facility in which the proposed biological product is manufactured, 
194  processed, packed, or held);15 
195   
196    A comprehensive and robust comparative analytical assessment between the proposed 
197  insulin product and the proposed reference product demonstrating that the proposed 
198  insulin product is highly similar to the reference product;16 
199   
200    A comparative clinical pharmacology study between the proposed insulin product and the 
201  reference product that provides a time-concentration profile and a time-action profile 
                                                 
13 See section 351(i)(2) of the PHS Act; see also, guidance for industry Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product (April 2015) for recommendations on determining biosimilarity, including 
considerations for demonstrating that a proposed product is highly similar to its reference product notwithstanding 
minor differences in clinically inactive components and that there are no clinically meaningful differences between 
the two products in terms of safety, purity, and potency. 
14 All product applications should contain a complete and thorough CMC section that provides appropriate 
information (e.g., characterization, adventitious agent safety, process controls, and specifications) necessary to 
support that the manufacturing process consistently delivers a product with the intended characteristics.  See e.g., 21 
CFR Parts 210, 211, 314, 600 through 680, and 820; guidances for industry, Q7 Good Manufacturing Practice 
Guidance for Active Pharmaceutical Ingredients (September 2016); Q7 Good Manufacturing Practice Guidance for 
Active Pharmaceutical Ingredients Questions and Answers (April 2018); Q11 Development and Manufacture of 
Drug Substances (November 2012); Q11 Development and Manufacture of Drug SubstancesQuestions and 
Answers (Chemical Entities and Biotechnological/Biological Entities) (February 2018); Submission of Chemistry, 
Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal 
Antibody Product for In Vivo Use (August 1996); and Process Validation:  General Principles and Practices 
(January 2011).  See also draft guidance for industry Development of Therapeutic Protein Biosimilars:  
Comparative Analytical Assessment and Other Quality-Related Considerations (May 2019).  This guidance, when 
finalized, will represent FDAs current thinking on that topic. 
15 Section 351(k)(2)(A)(i)(V) and (k)(3) of the PHS Act. 
16 See section 351(k)(2)(A)(i) of the PHS Act and guidance for industry Scientific Considerations in Demonstrating 
Biosimilarity to a Reference Product (April 2015).  As outlined in that guidance and in the draft guidance for 
industry Development of Therapeutic Protein Biosimilars:  Comparative Analytical Assessment and Other Quality-
Related Considerations (May 2019), this generally will include:  (1) comprehensive, robust comparative 
physicochemical and functional studies (these may include biological assays, binding assays, and enzyme kinetics) 
to evaluate the proposed product and the reference product; and (2) side-by-side analyses of an appropriate number 
of lots ( 10 lots of the reference product and  6 lots of the proposed product), where results are evaluated using 
pre-specified criteria.  This draft guidance, when finalized, will represent FDAs current thinking on this topic. 
 
  6 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
202  over the duration of action of each product based on reliable measures of systemic 
203  exposure and glucose response (e.g., glucose infusion rate), using an euglycemic clamp 
204  procedure or other appropriate test;17 and 
205   
206    An immunogenicity assessment justifying why a comparative clinical study to assess 
207  immunogenicity is not necessary to support a demonstration of biosimilarity.  This 
208  justification may reference other data and information in the application, e.g., the 
209  comparative analytical assessment with very low residual uncertainty described in the 
210  preceding section. 
211   
212  With regard to proposed interchangeable products, as described in the guidance for industry 
213  Considerations in Demonstrating Interchangeability With a Reference Product (May 2019), 
214  advances in analytics may allow for extended analytical characterization that affects the extent of 
215  other data and information needed to support a demonstration of interchangeability and may in 
216  certain circumstances lead to a more selective and targeted approach to clinical studies intended 
217  to support a demonstration of interchangeability.  Consistent with these statements in the 
218  guidance and the recommendations in this section, a comprehensive and robust comparative 
219  analytical assessment between a proposed interchangeable insulin product and the reference 
220  product demonstrating that the proposed interchangeable product is highly similar to the 
221  reference product with very low residual uncertainty about immunogenicity generally would 
222  mean that an applicant would not need to conduct a comparative clinical immunogenicity study, 
223  e.g., a switching study, to support licensure under section 351(k)(4) of the PHS Act so long as 
224  the statutory criteria for licensure as an interchangeable are otherwise met. 
 
225   
226  Applicants should consult with the Division of Metabolism and Endocrinology Products 
227  (DMEP) in the Office of New Drugs before submitting a 351(k) BLA to discuss any data and 
228  information that may be needed.  To determine whether a specific development program meets 
229  the criteria outlined in this guidance, an applicant should request a Biosimilar Biological Product 
230  Development (BPD) meeting, e.g., a Type 2 meeting for targeted advice based on substantive 
231  review of summary analytical data or a Type 3 meeting for an in-depth data review and 
232  recommendations regarding comprehensive analytical similarity data.18   
233   
234  IV.  CLINICAL EVALUATIONS OF IMMUNOGENICITY 
235   
236  The recommendations described above with regard to the need for comparative clinical 
237  immunogenicity studies are applicable when a proposed biosimilar or interchangeable insulin 
238  product is demonstrated to be highly similar, based upon a robust, comprehensive comparative 
239  analytic assessment to its proposed reference product such that there is little or no residual 
240  uncertainty related to clinical impact from immunogenicity.  In other circumstances, there may 
                                                 
17 See section 351(k)(2)(A)(i) of the PHS Act; see also guidance for industry Clinical Pharmacology Data to 
Support a Demonstration of Biosimilarity to a Reference Product (December 2016) for recommendations regarding 
exposure and response assessments to support a demonstration of biosimilarity.  
18 BsUFA II goals letter titled BsUFA Reauthorization Performance Goals and Procedures Fiscal Years 
2018 Through 2022 available on the FDA website at 
https://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM521121.pdf; draft 
guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products (June 
2018).  When final, this guidance will represent the FDAs current thinking on this topic.  
  7 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
241  be residual uncertainty regarding immunogenicity and a comparative clinical immunogenicity 
242  study may be needed to support a demonstration of biosimilarity or interchangeability.  For 
243  example, additional data, including possibly a comparative clinical immunogenicity study, may 
244  be necessary to support licensure of a proposed biosimilar or interchangeable insulin product for 
245  which differences in certain impurities or novel excipients give rise to questions or residual 
246  uncertainty related to immunogenicity.   
247   
248  If additional considerations relating to immunogenicity exist for a proposed product, licensure as 
249  a biosimilar or interchangeable under section 351(k) of the PHS Act may still be possible if such 
250  considerations are adequately addressed.  Contact the DMEP in the Office of New Drugs to 
251  discuss your proposed development program and to request a BPD meeting, as appropriate.   
252   
  8