Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

17065dft.doc
11/14/17
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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
1
Refuse to File: NDA and BLA Submissions to CDER	1
Guidance for Industry1
2
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
15
I. 	INTRODUCTION	16
17
The purpose of this guidance is to clarify circumstances under which the FDA’s Center for Drug	18
Evaluation and Research (CDER) may refuse to file a new drug application (NDA) or	19
supplemental NDA (21 CFR 314.101(d)) or a biologics license application (BLA) or	20
supplemental BLA (21 CFR 601.2) for a therapeutic biological product regulated by CDER,2 and	21
to underscore the importance of submitting a complete application to minimize the chance of a	22
refuse-to-file (RTF) action by the FDA. In particular, this guidance focuses on the FDA’s policy	23
for refusing to file an NDA under § 314.101(d)(3) when the NDA is incomplete because it does	24
not on its face contain information required under section 505(b) of the Federal Food, Drug, and	25
Cosmetic Act (FD&C Act) and 21 CFR 314.50.	26
27
This guidance does not address scenarios in which an application is incomplete under	28
§ 314.50(d)(3) because it does not on its face contain information required under sections 505(j)	29
and 507 of the FD&C Act or 21 CFR 314.94. Other circumstances under which the FDA may	30
refuse to file are described in § 314.101(d)(1), (2), and (4) through (9) and will not be discussed	31
in this guidance. 3 This guidance does not address refusal to file of abbreviated new drug	32
applications (ANDAs), 4 and it does not address refusal to file of an NDA for the regulatory	33
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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
deficiencies described in § 314.101(e). This guidance is not applicable to BLA submissions for	34
biological products regulated by the Center for Biologics Evaluation and Research.	35
36
This guidance also does not discuss the details of the format of an application required by	37
§ 314.50 or § 601.2 (NDA or BLA format) nor content required under 21 CFR 54.4(c) (financial	38
disclosure) (see the Appendix). Although missing or inadequate information to address the	39
requirements under section 505(b) of the FD&C Act and § 314.50 can be the basis for refusal to	40
file an NDA discussed in the guidance, the specific format requirements detailed in § 314.50 will	41
not be further described in this guidance. Because administrative filing procedures are well	42
understood, this guidance is limited to consideration of whether an application is incomplete on	43
its face for purposes of refusal to file.5
	44
45
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	46
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	47
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	48
the word should in Agency guidances means that something is suggested or recommended, but	49
not required.	50
51
52
II. 	BACKGROUND	53
54
The FDA will file an NDA within 60 days of receipt or inform the applicant of the refusal to	55
file.6 The FDA generally makes filing determinations for BLAs within the same time frame.	56
Filing an application means that the FDA has made a threshold determination that the application	57
is sufficiently complete to permit a substantive review.7
	58
59
FDA regulations describe the possibility that the FDA will consider an application to be	60
deficient, on its face, in a way that precludes a complete review (see §§ 314.101(d) and	61
601.2(a)). Specifically, § 314.101(d)(3) provides that the FDA may refuse to file an NDA if:	62
63
“The NDA . . . is incomplete because it does not on its face contain information required	64
under section 505(b) . . . of the Federal Food, Drug, and Cosmetic Act and § 314.50 . . . .”	65
66
When this is the case, the FDA may not accept the application for review and may refuse to file	67
it.8
	68
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 CDER’s 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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
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Since the early 1990s, the FDA’s processes and timelines for reviewing newly submitted	70
applications have substantially evolved. The administrative complexity of applications, with	71
corresponding complexity in determinations of application completeness, has increased. For an	72
NDA for a new molecular entity (NME) or an original BLA regulated by CDER, the PDUFA	73
Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 established	74
a review model (referred to as the Program) to promote greater transparency and to improve	75
communication between the FDA and the applicant during the review of such applications.9
	76
77
When discussing the planned submission of these applications at a presubmission meeting, the	78
FDA and the applicant reach agreements regarding the content of a complete application for the	79
proposed indication(s) as well as agreements, if any, on submission of minor components that	80
may be submitted not later than 30 calendar days after submission of the original application.	81
Unless the applicant and the FDA have agreed at the presubmission meeting to delayed	82
submission of certain components of the application, the FDA expects applications to be	83
complete at the time of submission.10 If agreed-upon delayed minor components are not	84
received within 30 calendar days after receipt of the original application, the application will be	85
considered incomplete. Incomplete applications may be refused for filing. A rolling review	86
permitted under fast track designation has similar obligations.11
	87
88
Documenting agreements reached at presubmission meetings for drug products that are part of	89
the Program, then ensuring that only agreed-upon components are submitted after receipt of the	90
original application and that these agreed-upon components are received within the 30-day	91
window and are complete, has added significant complexity to a determination that an	92
application is complete.	93
94
The FDA has also committed to timely review of applications under the Prescription Drug User	95
Fee Act. The overall goal is to efficiently and effectively review applications, and thus it is	96
critical to avoid use of resources to review an application when necessary components are so	97
facially deficient as to render them incomplete. The FDA exercises its RTF authority for	98
incomplete applications to optimize the use of both the applicant’s and the FDA’s resources.	99
RTF actions allow the FDA to notify applicants of application deficiencies as soon as possible,	100
rather than waiting until the end of a review cycle and notifying the applicant in a complete	101
response letter. This process can lead to more rapid approval of safe and effective drug and	102
biological products.	103
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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
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III. 	PROCESS AND PROCEDURES	106
107
A. 	Filing Review and Assessment	108
109
The FDA’s initial assessment of a submitted application focuses heavily on assessing the	110
completeness of the application, because incompleteness can lead to refusal to file. Before	111
commencing review of an application, it is important for the FDA to be assured that there will in	112
fact be a complete application that can be reviewed. An application may be considered	113
incomplete for purposes of § 314.101(d)(3) based on deficiencies that on their face render an	114
application incomplete, including applications that are unreviewable or inconsistent with	115
statutory or regulatory requirements.	116
117
During the filing review, FDA staff may also identify certain review issues that result in a refusal	118
to file pursuant to § 314.101(d)(3) and other authorities.12 Review issues typically are not	119
usually considered the basis for an RTF action but are communicated to applicants in official	120
filing correspondence, including RTF letters. However, some review issues may render an	121
application incomplete and may therefore result in a refusal to file.	122
123
To make filing determinations, FDA staff assess the completeness of an application and	124
determine the extent and type of deficiencies, if any, by considering the significance of the	125
missing or incomplete information in the context of the proposed drug product, the proposed	126
indication(s), and the amount of time needed to address any given deficiency. Filing issues	127
generally are grouped into two categories as follows:	128
129
(1) Potentially easily correctable deficiencies, which applicants typically can correct before	130
filing. This category is not discussed further in this guidance.	131
132
(2) Complex significant deficiencies that cannot be corrected before filing and that may	133
result in a refusal to file pursuant to § 314.101(d)(3) and other authorities. Examples of	134
such deficiencies include, but are not limited to:	135
136
(a) Materially lacking or inadequately organized applications that would not permit	137
timely, efficient, and complete review by all relevant review division disciplines as	138
outlined in the guidance for review staff and industry Good Review Management	139
Principles and Practices for PDUFA Products.	140
141
(b) Parts of applications that contain inadequate information for one or more indications	142
when multiple indications are submitted in the same application. The FDA may	143
accept for filing those parts of an application that represent complete submissions for	144
particular indications but refuse to file those parts that are determined to be	145
incomplete for other indications.	146
147
(c) An application that relies on a single adequate and well-controlled trial for a	148
demonstration of effectiveness if prior communication between the FDA and the	149
applicant (i.e., end-of-phase 2 meeting) determined the need for more than one trial to	150
12 See MAPP 6025.4 Good Review Practice: Refuse to File.

Contains Nonbinding Recommendations
Draft — Not for Implementation
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demonstrate effectiveness and if the submitted justification for reliance on a single	151
trial is inadequate. (The FDA may determine that data from a single adequate and	152
well-controlled trial and confirmatory evidence is sufficient to establish effectiveness	153
(see section 505(d) of the FD&C Act); this is further discussed in the guidance for	154
industry Providing Clinical Evidence of Effectiveness for Human Drug and	155
Biological Products.)	156
157
(d) Failure to submit an assessment of studies related to the potential abuse of a drug,	158
necessary to inform drug scheduling under the Controlled Substances Act and the	159
development of drug product labeling. This requirement applies when the drug	160
affects the central nervous system (as determined in animal or human studies), is	161
chemically or pharmacologically similar to other drugs with known abuse potential	162
(such as an opioid, stimulant, depressant, or hallucinogen), or produces psychoactive	163
effects such as euphoria, mood changes, depression, or hallucinations. See	164
§ 314.50(d)(5)(vii) and the guidance for industry Assessment of Abuse Potential of	165
Drugs.	166
167
(e) Required content is not submitted electronically where the FDA has specified the	168
format of such submissions in guidance pursuant to section 745A of the FD&C Act or	169
required content is not submitted in an electronic format that the FDA can review,	170
process, and archive, where such electronic submissions are required by an applicable	171
regulation.13 Electronic submission issues that CDER considers to be filing issues	172
include particular organization, file format, coding, or formatting problems that are	173
specified in applicable guidances issued pursuant to section 745A(a) of the FD&C	174
Act.14
	175
176
(f) NME NDAs or original BLAs reviewed under the Program, if the minor components	177
agreed upon for late submission at the presubmission meeting are not received within	178
30 calendar days after receipt of the application.	179
180
B. 	FDA Decision-Making and Notification to the Applicant	181
182
After completion of the filing reviews and discussion of the reviews at an internal filing meeting,	183
the division director (or designee) of the relevant review division makes the final filing decision.	184
If the division director (or designee) determines that an application cannot be filed, the review	185
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/.

Contains Nonbinding Recommendations
Draft — Not for Implementation
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division will communicate an RTF action to the applicant by day 60 in the form of official	186
correspondence.	187
188
C. 	Applicant Response	189
190
Within 30 days of the date of the review division’s RTF notification, the applicant may request	191
in writing an informal conference with the FDA to discuss whether the FDA should file the	192
application.	193
194
In general, the review division will grant an informal conference request if submitted within the	195
30-day time frame described above.15 If, after the informal conference, the applicant requests	196
that the review division file the application (with or without amendments to correct the	197
deficiencies), the review division will file the application over protest pursuant to	198
§ 314.101(a)(3), notify the applicant in writing, and review it as filed. The applicant need not	199
resubmit a copy of an application filed over protest. If an NDA is filed over protest, the filing	200
date will be designated as 60 days after the receipt date of the informal conference meeting	201
request.16 Applications for NME NDAs or original BLAs received between October 1, 2012,	202
through September 30, 2017, that are filed over protest will not be reviewed under the Program.17
	203
Alternatively, the applicant may amend the NDA and resubmit it, and the review division will	204
make a separate determination whether the resubmitted NDA may be filed.18
	205
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).

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APPENDIX: SELECT REFUSE-TO-FILE AUTHORITIES	207
208
The authorities relevant to refusal to file a new drug application (NDA) 19 or biologics license	209
application (BLA) include, but may not be limited to, the following sections of the Code of	210
Federal Regulations:	211
212
 	21 CFR 314.50, content and format of NDAs	213
214
 	21 CFR 601.2(a), applications for biologics licenses; procedures for filing	215
216
 	21 CFR 54.4(c), financial disclosure requirements	217
218
‒ 	The FDA may refuse to file any marketing application that does not contain the	219
information required by this section or a certification by the applicant that the applicant	220
has acted with due diligence to obtain the information but was unable to do so and stating	221
the reason	222
223
 	21 CFR 314.101(d)(1) through (9), NDA deficiencies (in relevant part)	224
225
‒ 	The NDA does not contain a completed application form (§ 314.101(d)(1))	226
227
‒ 	The NDA is not submitted in the form required under § 314.50 (§ 314.101(d)(2))	228
229
‒ 	The NDA is incomplete because it does not on its face contain information required	230
under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act),	231
§ 314.50, or other enumerated provisions (§ 314.101(d)(3))	232
233
‒ 	The applicant fails to submit a complete environmental assessment, which addresses each	234
of the items specified in the applicable format under 21 CFR 25.40 or fails to provide	235
sufficient information to establish a categorical exclusion under 21 CFR 25.30 or 21 CFR	236
25.31 (§ 314.101(d)(4))	237
238
‒ 	The NDA does not contain an accurate and complete English translation of each part of	239
the NDA that is not in English (§ 314.101(d)(5))	240
241
‒ 	The NDA does not contain a statement for each nonclinical laboratory study that the	242
study was conducted in compliance with the requirements set forth in 21 CFR part 58, or,	243
for each study not conducted in compliance with part 58, a brief statement of the reason	244
for the noncompliance (§ 314.101(d)(6))	245
246
‒ 	The NDA does not contain a statement for each clinical study that the study was	247
conducted in compliance with the institutional review board regulations in 21 CFR part	248
56, or was not subject to those regulations, and that it was conducted in compliance with	249
the informed consent regulations in 21 CFR part 50, or, if the study was subject to but	250
19 See also 21 CFR 314.101(e).

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was not conducted in compliance with those regulations, the NDA does not contain a	251
brief statement of the reason for the noncompliance (§ 314.101(d)(7))	252
253
‒ 	The drug product that is the subject of the submission is already covered by an approved	254
NDA or abbreviated new drug application (ANDA) and the applicant of the submission:	255
(1) has an approved NDA or ANDA for the same drug product; or (2) is merely a	256
distributor and/or repackager of the already approved drug product (§ 314.101(d)(8))	257
258
‒ 	The NDA is submitted as a 505(b)(2) application for a drug product that is a duplicate of	259
a listed drug and is eligible for approval under section 505(j) of the FD&C Act	260
(§ 314.101(d)(9))20
	261
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.