Refuse to File:  NDA 
and BLA Submissions 
to CDER 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Amalia Himaya at 301-796-0700.  
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2017 
Procedural 
 
17065dft.doc 
11/14/17   
Refuse to File:  NDA 
and BLA Submissions 
to CDER 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2017 
Procedural 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  PROCESS AND PROCEDURES .................................................................................... 4 
A.  Filing Review and Assessment ...................................................................................................... 4 
B.  FDA Decision-Making and Notification to the Applicant .......................................................... 5 
C.  Applicant Response ........................................................................................................................ 6 
APPENDIX:  SELECT REFUSE-TO-FILE AUTHORITIES ................................................. 7 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Refuse to File:  NDA and BLA Submissions to CDER 
1 
Guidance for Industry1 
2 
3   
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   
15   
16  I.  INTRODUCTION  
17   
18  The purpose of this guidance is to clarify circumstances under which the FDAs Center for Drug 
19  Evaluation and Research (CDER) may refuse to file a new drug application (NDA) or 
20  supplemental NDA (21 CFR 314.101(d)) or a biologics license application (BLA) or 
21  supplemental BLA (21 CFR 601.2) for a therapeutic biological product regulated by CDER,2 and 
22  to underscore the importance of submitting a complete application to minimize the chance of a 
23  refuse-to-file (RTF) action by the FDA.  In particular, this guidance focuses on the FDAs policy 
24  for refusing to file an NDA under  314.101(d)(3) when the NDA is incomplete because it does 
25  not on its face contain information required under section 505(b) of the Federal Food, Drug, and 
26  Cosmetic Act (FD&C Act) and 21 CFR 314.50.   
27   
28  This guidance does not address scenarios in which an application is incomplete under 
29   314.50(d)(3) because it does not on its face contain information required under sections 505(j) 
30  and 507 of the FD&C Act or 21 CFR 314.94.  Other circumstances under which the FDA may 
31  refuse to file are described in  314.101(d)(1), (2), and (4) through (9) and will not be discussed 
32  in this guidance.3  This guidance does not address refusal to file of abbreviated new drug 
33  applications (ANDAs),4 and it does not address refusal to file of an NDA for the regulatory 
                                                 
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration.  
 
2 For BLAs,  601.2(a) states that a BLA shall not be considered as filed until all pertinent information and data 
have been received by the Food and Drug Administration.  
 
3 Specific examples of RTF scenarios also can be found in MAPP 6025.4 Good Review Practice:  Refuse to File 
available on the Manual of Policies and Procedures web page at 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm. 
 
4 See the guidance for industry ANDA Submissions  Refuse-to-Receive Standards.  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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  1 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34  deficiencies described in  314.101(e).  This guidance is not applicable to BLA submissions for 
35  biological products regulated by the Center for Biologics Evaluation and Research. 
36   
37  This guidance also does not discuss the details of the format of an application required by 
38   314.50 or  601.2 (NDA or BLA format) nor content required under 21 CFR 54.4(c) (financial 
39  disclosure) (see the Appendix).  Although missing or inadequate information to address the 
40  requirements under section 505(b) of the FD&C Act and  314.50 can be the basis for refusal to 
41  file an NDA discussed in the guidance, the specific format requirements detailed in  314.50 will 
42  not be further described in this guidance.  Because administrative filing procedures are well 
43  understood, this guidance is limited to consideration of whether an application is incomplete on 
44  its face for purposes of refusal to file.5 
45   
46  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
47  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
48  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
49  the word should in Agency guidances means that something is suggested or recommended, but 
50  not required.  
51   
52   
53  II.  BACKGROUND 
54   
55  The FDA will file an NDA within 60 days of receipt or inform the applicant of the refusal to 
56  file.6  The FDA generally makes filing determinations for BLAs within the same time frame.  
57  Filing an application means that the FDA has made a threshold determination that the application 
58  is sufficiently complete to permit a substantive review.7 
59   
60  FDA regulations describe the possibility that the FDA will consider an application to be 
61  deficient, on its face, in a way that precludes a complete review (see  314.101(d) and 
62  601.2(a)).  Specifically,  314.101(d)(3) provides that the FDA may refuse to file an NDA if:   
63   
64  The NDA . . . is incomplete because it does not on its face contain information required 
65  under section 505(b) . . . of the Federal Food, Drug, and Cosmetic Act and  314.50 . . . .   
66   
67  When this is the case, the FDA may not accept the application for review and may refuse to file 
68  it.8   
69   
                                                 
5 On May 19, 2017, the FDA withdrew its previously published guidance for industry Refusal to File (issued July 
12, 1993).  The FDA is issuing this guidance to update and clarify CDERs procedures for determining whether an 
application should be refused for filing because it is incomplete on its face.  This guidance includes procedures for 
certain BLAs and supplemental BLAs, given that CDER has regulatory responsibility for certain therapeutic 
biological products subject to licensing under the Public Health Service Act. 
 
6 See  314.101(a). 
 
7 See  314.101(a)(1) (regarding NDAs). 
 
8 See section III.C., Applicant Response, for a description of filing over protest. 
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
70  Since the early 1990s, the FDAs processes and timelines for reviewing newly submitted 
71  applications have substantially evolved.  The administrative complexity of applications, with 
72  corresponding complexity in determinations of application completeness, has increased.  For an 
73  NDA for a new molecular entity (NME) or an original BLA regulated by CDER, the PDUFA 
74  Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 established 
75  a review model (referred to as the Program) to promote greater transparency and to improve 
76  communication between the FDA and the applicant during the review of such applications.9   
77   
78  When discussing the planned submission of these applications at a presubmission meeting, the 
79  FDA and the applicant reach agreements regarding the content of a complete application for the 
80  proposed indication(s) as well as agreements, if any, on submission of minor components that 
81  may be submitted not later than 30 calendar days after submission of the original application.  
82  Unless the applicant and the FDA have agreed at the presubmission meeting to delayed 
83  submission of certain components of the application, the FDA expects applications to be 
84  complete at the time of submission.10  If agreed-upon delayed minor components are not 
85  received within 30 calendar days after receipt of the original application, the application will be 
86  considered incomplete.  Incomplete applications may be refused for filing.  A rolling review 
87  permitted under fast track designation has similar obligations.11    
88   
89  Documenting agreements reached at presubmission meetings for drug products that are part of 
90  the Program, then ensuring that only agreed-upon components are submitted after receipt of the 
91  original application and that these agreed-upon components are received within the 30-day 
92  window and are complete, has added significant complexity to a determination that an 
93  application is complete.   
94   
95  The FDA has also committed to timely review of applications under the Prescription Drug User 
96  Fee Act.  The overall goal is to efficiently and effectively review applications, and thus it is 
97  critical to avoid use of resources to review an application when necessary components are so 
98  facially deficient as to render them incomplete.  The FDA exercises its RTF authority for 
99  incomplete applications to optimize the use of both the applicants and the FDAs resources.  
100  RTF actions allow the FDA to notify applicants of application deficiencies as soon as possible, 
101  rather than waiting until the end of a review cycle and notifying the applicant in a complete 
102  response letter.  This process can lead to more rapid approval of safe and effective drug and 
103  biological products. 
104   
105   
                                                 
9 See https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm327030.htm. 
 
10 See the PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 
(https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm149212.htm). 
 
11 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
  3 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106  III.  PROCESS AND PROCEDURES 
107   
108  A.  Filing Review and Assessment 
109   
110  The FDAs initial assessment of a submitted application focuses heavily on assessing the 
111  completeness of the application, because incompleteness can lead to refusal to file.  Before 
112  commencing review of an application, it is important for the FDA to be assured that there will in 
113  fact be a complete application that can be reviewed.  An application may be considered 
114  incomplete for purposes of  314.101(d)(3) based on deficiencies that on their face render an 
115  application incomplete, including applications that are unreviewable or inconsistent with 
116  statutory or regulatory requirements.    
117   
118  During the filing review, FDA staff may also identify certain review issues that result in a refusal 
119  to file pursuant to  314.101(d)(3) and other authorities.12  Review issues typically are not 
120  usually considered the basis for an RTF action but are communicated to applicants in official 
121  filing correspondence, including RTF letters.  However, some review issues may render an 
122  application incomplete and may therefore result in a refusal to file.   
123   
124  To make filing determinations, FDA staff assess the completeness of an application and 
125  determine the extent and type of deficiencies, if any, by considering the significance of the 
126  missing or incomplete information in the context of the proposed drug product, the proposed 
127  indication(s), and the amount of time needed to address any given deficiency.  Filing issues 
128  generally are grouped into two categories as follows: 
129   
130  (1) Potentially easily correctable deficiencies, which applicants typically can correct before 
131  filing.  This category is not discussed further in this guidance. 
132   
133  (2) Complex significant deficiencies that cannot be corrected before filing and that may 
134  result in a refusal to file pursuant to  314.101(d)(3) and other authorities.  Examples of 
135  such deficiencies include, but are not limited to: 
136   
137  (a) Materially lacking or inadequately organized applications that would not permit 
138  timely, efficient, and complete review by all relevant review division disciplines as 
139  outlined in the guidance for review staff and industry Good Review Management 
140  Principles and Practices for PDUFA Products.   
141   
142  (b) Parts of applications that contain inadequate information for one or more indications 
143  when multiple indications are submitted in the same application.  The FDA may 
144  accept for filing those parts of an application that represent complete submissions for 
145  particular indications but refuse to file those parts that are determined to be 
146  incomplete for other indications.  
147   
148  (c) An application that relies on a single adequate and well-controlled trial for a 
149  demonstration of effectiveness if prior communication between the FDA and the 
150  applicant (i.e., end-of-phase 2 meeting) determined the need for more than one trial to 
                                                 
12 See MAPP 6025.4 Good Review Practice:  Refuse to File.  
  4 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
151  demonstrate effectiveness and if the submitted justification for reliance on a single 
152  trial is inadequate.  (The FDA may determine that data from a single adequate and 
153  well-controlled trial and confirmatory evidence is sufficient to establish effectiveness 
154  (see section 505(d) of the FD&C Act); this is further discussed in the guidance for 
155  industry Providing Clinical Evidence of Effectiveness for Human Drug and 
156  Biological Products.) 
157   
158  (d) Failure to submit an assessment of studies related to the potential abuse of a drug, 
159  necessary to inform drug scheduling under the Controlled Substances Act and the 
160  development of drug product labeling.  This requirement applies when the drug 
161  affects the central nervous system (as determined in animal or human studies), is 
162  chemically or pharmacologically similar to other drugs with known abuse potential 
163  (such as an opioid, stimulant, depressant, or hallucinogen), or produces psychoactive 
164  effects such as euphoria, mood changes, depression, or hallucinations.  See 
165   314.50(d)(5)(vii) and the guidance for industry Assessment of Abuse Potential of 
166  Drugs. 
167   
168  (e) Required content is not submitted electronically where the FDA has specified the 
169  format of such submissions in guidance pursuant to section 745A of the FD&C Act or 
170  required content is not submitted in an electronic format that the FDA can review, 
171  process, and archive, where such electronic submissions are required by an applicable 
172  regulation.13  Electronic submission issues that CDER considers to be filing issues 
173  include particular organization, file format, coding, or formatting problems that are 
174  specified in applicable guidances issued pursuant to section 745A(a) of the FD&C 
175  Act.14   
176   
177  (f) NME NDAs or original BLAs reviewed under the Program, if the minor components 
178  agreed upon for late submission at the presubmission meeting are not received within 
179  30 calendar days after receipt of the application.  
180   
181  B.  FDA Decision-Making and Notification to the Applicant 
182   
183  After completion of the filing reviews and discussion of the reviews at an internal filing meeting, 
184  the division director (or designee) of the relevant review division makes the final filing decision.  
185  If the division director (or designee) determines that an application cannot be filed, the review 
                                                 
13 See, for example, 21 CFR 314.80(g) and the guidance for industry Providing Regulatory Submissions in 
Electronic Format  Certain Human Pharmaceutical Product Applications and Related Submissions Using the 
eCTD Specifications as follows:  A submission that is not in the electronic format(s) described in this guidance 
document will not be filed or received, unless it has been exempted from the electronic submission requirements 
(see section III.C) with respect to that submission.   
 
14 For more information about electronic submissions, applicants should refer to the guidance for industry Providing 
Regulatory Submissions in Electronic Format  Certain Human Pharmaceutical Product Applications and Related 
Submissions Using the eCTD Specifications.  The FDA also posts detailed information about electronic submissions 
periodically on the Electronic Submissions Gateway web page at 
https://www.fda.gov/forindustry/electronicsubmissionsgateway/. 
  5 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
186  division will communicate an RTF action to the applicant by day 60 in the form of official 
187  correspondence.    
188   
189  C.  Applicant Response 
190   
191  Within 30 days of the date of the review divisions RTF notification, the applicant may request 
192  in writing an informal conference with the FDA to discuss whether the FDA should file the 
193  application. 
194   
195  In general, the review division will grant an informal conference request if submitted within the 
196  30-day time frame described above.15  If, after the informal conference, the applicant requests 
197  that the review division file the application (with or without amendments to correct the 
198  deficiencies), the review division will file the application over protest pursuant to 
199   314.101(a)(3), notify the applicant in writing, and review it as filed.  The applicant need not 
200  resubmit a copy of an application filed over protest.  If an NDA is filed over protest, the filing 
201  date will be designated as 60 days after the receipt date of the informal conference meeting 
202  request.16  Applications for NME NDAs or original BLAs received between October 1, 2012, 
203  through September 30, 2017, that are filed over protest will not be reviewed under the Program.17  
204  Alternatively, the applicant may amend the NDA and resubmit it, and the review division will 
205  make a separate determination whether the resubmitted NDA may be filed.18 
206   
                                                 
15 See  314.101(a)(3) (regarding NDAs).  CDER grants informal conference requests submitted within the same 
time frame for BLAs. 
 
16 Id. 
 
17 See the PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 
(https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm149212.htm). 
 
18 See  314.101(a)(3). 
  6 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
207  APPENDIX:  SELECT REFUSE-TO-FILE AUTHORITIES 
208   
209  The authorities relevant to refusal to file a new drug application (NDA)19 or biologics license 
210  application (BLA) include, but may not be limited to, the following sections of the Code of 
211  Federal Regulations: 
212   
213    21 CFR 314.50, content and format of NDAs 
214   
215    21 CFR 601.2(a), applications for biologics licenses; procedures for filing 
216   
217    21 CFR 54.4(c), financial disclosure requirements 
218   
219    The FDA may refuse to file any marketing application that does not contain the 
220  information required by this section or a certification by the applicant that the applicant 
221  has acted with due diligence to obtain the information but was unable to do so and stating 
222  the reason 
223   
224    21 CFR 314.101(d)(1) through (9), NDA deficiencies (in relevant part) 
225   
226    The NDA does not contain a completed application form ( 314.101(d)(1))  
227   
228    The NDA is not submitted in the form required under  314.50 ( 314.101(d)(2)) 
229   
230    The NDA is incomplete because it does not on its face contain information required 
231  under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 
232   314.50, or other enumerated provisions ( 314.101(d)(3)) 
233   
234    The applicant fails to submit a complete environmental assessment, which addresses each 
235  of the items specified in the applicable format under 21 CFR 25.40 or fails to provide 
236  sufficient information to establish a categorical exclusion under 21 CFR 25.30 or 21 CFR 
237  25.31 ( 314.101(d)(4)) 
238   
239    The NDA does not contain an accurate and complete English translation of each part of 
240  the NDA that is not in English ( 314.101(d)(5)) 
241   
242    The NDA does not contain a statement for each nonclinical laboratory study that the 
243  study was conducted in compliance with the requirements set forth in 21 CFR part 58, or, 
244  for each study not conducted in compliance with part 58, a brief statement of the reason 
245  for the noncompliance ( 314.101(d)(6)) 
246   
247    The NDA does not contain a statement for each clinical study that the study was 
248  conducted in compliance with the institutional review board regulations in 21 CFR part 
249  56, or was not subject to those regulations, and that it was conducted in compliance with 
250  the informed consent regulations in 21 CFR part 50, or, if the study was subject to but 
                                                 
19 See also 21 CFR 314.101(e). 
  7 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
251  was not conducted in compliance with those regulations, the NDA does not contain a 
252  brief statement of the reason for the noncompliance ( 314.101(d)(7)) 
253   
254    The drug product that is the subject of the submission is already covered by an approved 
255  NDA or abbreviated new drug application (ANDA) and the applicant of the submission:  
256  (1) has an approved NDA or ANDA for the same drug product; or (2) is merely a 
257  distributor and/or repackager of the already approved drug product ( 314.101(d)(8)) 
258   
259    The NDA is submitted as a 505(b)(2) application for a drug product that is a duplicate of 
260  a listed drug and is eligible for approval under section 505(j) of the FD&C Act 
261  ( 314.101(d)(9))20 
262   
                                                 
20 The term duplicate generally refers to a drug product that is the same as a listed drug with respect to active 
ingredient(s), dosage form, strength, route of administration, and conditions of use, among other characteristics.  The 
FDA intends to consider on a case-by-case basis any assertions by a prospective 505(b)(2) applicant that there is 
uncertainty about whether a listed drug contains the same active ingredient as the proposed drug product.  
  8