Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry

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

58687461fnlrv8.docx
Providing Regulatory Submissions
in Electronic Format — Certain
Human Pharmaceutical Product
Applications and Related
Submissions Using the eCTD
Specifications
Guidance for Industry
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)
September 2024
Electronic Submissions
Revision 8

Providing Regulatory Submissions
in Electronic Format — Certain
Human Pharmaceutical Product
Applications and Related
Submissions Using the eCTD
Specifications
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., 4 th 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
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
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)
September 2024
Electronic Submissions
Revision 8

RELATED DOCUMENTS
Technical specifications associated with this guidance are provided as separate documents
and are updated periodically. A list of documents cited within this guidance are provided
at the end of this document.
For a complete list of all documents and supportive files needed to submit electronically,
refer to the eCTD web page at https://www.fda.gov/drugs/electronic-regulatory-submission-
and-review/electronic-common-technical-document-ectd.
REVISION HISTORY
DATE 	S UMMARY OF R EVISIONS
April 2017
Update to Guidance
Section I. Introduction
• 	Added paragraph describing rationale for changing timetable for required
master file submissions in eCTD from 24 months to 36 months
Section III.B. Timetable for Implementation of Electronic Submission Requirements
• 	Updated section to reflect that the requirement for master files to be filed
electronically takes effect 36 months after May 5, 2015
• 	Updated example of timetable to reflect actual timetable for the implementation
of the electronic submissions requirement
April 2018
Update to Guidance
Section I. Introduction
• 	Added paragraph describing rationale for extending timetable for Type III drug
master file submissions in eCTD for an additional 12 months
Section III.A. Types of Submissions That Must Adhere to the Electronic Submission
Requirement Described in This Guidance
• 	Revised paragraph to reflect change in nomenclature of “biologic product files
(BPFs)” to “other master files relevant to a biological product”
Section III.B. Timetable for Implementation of Electronic Submission Requirements
• 	Updated section to reflect that the requirement for Type III drug master files to
be filed electronically takes place 48 months after May 5, 2015
Updated example of timetable to reflect actual timetable for the implementation of the
electronic submissions requirement

DATE 	S UMMARY OF R EVISIONS
January 2019
Update to Guidance
Section I. Introduction
• 	Added paragraph describing rationale for extending timetable for Type III drug
master file submissions in eCTD for an additional 12 months
Section III.B. Timetable for Implementation of Electronic Submission Requirements
• 	Updated section to reflect that the requirement for Type III drug master files to
be filed electronically takes place 60 months after May 5, 2015
• 	Updated example of timetable to reflect actual timetable for the implementation
of the electronic submissions requirement
February 2020
Update to Guidance
Section I. Introduction
• 	Added paragraph describing the addition of exemptions and waivers from
complying with eCTD requirements
Section III.C. Types of Submissions That Are Exempted From the eCTD Requirement
Described in This Guidance
• 	Updated section to include exemption for Type III drug master files
Section III.D. Types of Submissions That May Qualify for a Long-Term Waiver From
the eCTD Requirement Described in This Guidance
• 	Added section to include waiver criteria for certain PET drug INDs, NDAs,
ANDAs, and BLAs, and waiver criteria for certain Type II DMFs
Section III.E. Types of Submissions That May Qualify for a Short-Term Waiver From
the eCTD Requirement Described in This Guidance
• 	Added section to include the criteria to qualify for a waiver and the instructions
on how to submit a request for a short-term waiver
September 2024
General
• 	Updated hyperlinks throughout guidance
Section III.F. The eCTD Specifications
Section III.H. Submission Structure: Granularity, Files, and Folders
Section III.J. Document Life Cycle
Section III.L. Datasets and Study Information
⦁ 	Updated sections (III.F, H, J, and L) to include eCTD v4.0

D ATE 	S UMMARY OF R EVISIONS
Section IV. Technical Specification Documents Referenced in This Guidance
⦁ 	Updated section to include eCTD v4.0-related documents

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE3
A. 	Types of Submissions That Must Adhere to the Electronic Submission Requirement
Described in This Guidance ................................................................................................................... 3
B. 	Timetable for Implementation of Electronic Submission Requirements.................................. 4
C. 	Types of Submissions Exempted From the eCTD Requirement Described in This Guidance6
D. 	Certain Positron Emission Tomography Drugs and Type II DMF Submissions That May
Qualify for a Waiver From the eCTD Requirement Described in This Guidance ........................... 6
1. Certain Positron Emission Tomography Drug Submissions ........................................................... 7
2. Certain Type II DMF Submissions .................................................................................................. 8
3. Where to Submit Waiver Requests ................................................................................................... 8
4. FDA Response to Waiver Requests .................................................................................................. 9
E. 	Types of Submissions That May Qualify for a Short-Term Waiver From the eCTD
Requirement Described in This Guidance ........................................................................................... 9
1. Content of Waiver Requests ........................................................................................................... 10
2. Where to Submit Waiver Requests ................................................................................................. 10
3. FDA Response to Waiver Requests ................................................................................................ 11
F. 	The eCTD Specifications ............................................................................................................. 11
G. 	Pre-Submission Considerations .................................................................................................. 12
H. 	Submission Structure: Granularity, Files, and Folders .......................................................... 12
I. 	File Formats and Versions .......................................................................................................... 13
J. 	Document Life Cycle.................................................................................................................... 14
K. 	Summary of Clinical Efficacy and Summary of Clinical Safety.............................................. 14
L. 	Datasets and Study Information ................................................................................................. 14
M. 	Transmitting Electronic Submissions ........................................................................................ 15
N. 	FDA Forms ................................................................................................................................... 15
O. 	Restrictions on Submission of Paper Copies ............................................................................. 15
P. 	Receipt Date.................................................................................................................................. 15
IV. 	TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS
GUIDANCE ................................................................................................................................. 16
V. 	RELATED REFERENCES ........................................................................................... 17

1
Providing Regulatory Submissions in Electronic Format — Certain	1
Human Pharmaceutical Product1 Applications and Related	2
Submissions Using the eCTD Specifications	3
Guidance for Industry2
4
5
6
I. 	INTRODUCTION	7
8
Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least	9
24 months after the issuance of a final guidance document in which the Food and Drug	10
Administration (FDA or Agency) has specified the electronic format for submitting submission	11
types to the Agency, such content must be submitted electronically and in the format specified by	12
FDA.3,4 This guidance describes how sponsors and applicants must organize the content that	13
they submit to the Agency electronically for all submission types under section 745A(a) of the	14
FD&C Act. This guidance also references several technical specification documents5 and the	15
Electronic Common Technical Document Conformance (eCTD) Guide, which provide additional	16
details regarding the organization of content for electronic submissions.6	
17
18
This guidance implements the electronic submission requirements of section 745A(a) of the	19
FD&C Act for the electronic format of the content submitted in new drug applications (NDAs),	20
abbreviated new drug applications (ANDAs), certain biologics license applications (BLAs), and	21
1 The term human pharmaceutical product, as used in this guidance, includes any product intended for human use
that meets the definition of drug and does not also meet the definition of device under the Federal Food, Drug, and
Cosmetic Act (FD&C Act), including both (1) drugs approved under the FD&C Act and (2) biological products
approved under the Public Health Service Act (PHS Act). Similarly, for the purposes of this guidance, unless
otherwise specified, the term drug refers to human prescription drugs, including those that are licensed as biological
products (biologics).
2 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for
Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).
3 See 21 U.S.C. 379k–1.
4 For additional information on how FDA interprets and intends to implement the electronic submission
requirements of section 745A(a) of the FD&C Act, please see the guidance for industry Providing Regulatory
Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic
Act (December 2014). We update guidances periodically. For the most recent version of a guidance, check the
FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
5 For instance, to reflect the evolving nature of the technology and the experience of those using this technology, the
electronic common technical document (eCTD) technical specifications are being provided as separate documents in
connection with this guidance. These associated specifications will be updated periodically. For the most recent
versions of related technical specifications (CDER and CBER), check the eCTD web page at
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-
ectd.
6 For the most recent version of the eCTD Technical Conformance Guide, check the eCTD Resources web page at
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources.

2
certain investigational new drug applications (INDs) to the Center for Drug Evaluation and	22
Research (CDER) or to the Center for Biologics Evaluation and Research (CBER). See section	23
III.A of this guidance for more information regarding required submission types. Submissions	24
that are not submitted electronically and electronic submissions that are not in a format that FDA	25
can process, review, and archive will not be filed or received unless they have an exemption or	26
waiver from the electronic submission requirements.	27
28
The revised guidance was issued on May 5, 2015, and provided a timetable of 24 months after	29
issuance of the final guidance for the initial implementation of the electronic submission	30
requirement for NDAs, ANDAs, BLAs, and master files (May 5, 2017) and 36 months for	31
commercial INDs (May 5, 2018). The timetable indicated that NDAs, BLAs, ANDAs, and	32
master files were to be submitted electronically in eCTD format starting on May 5, 2017 (May 5,	33
2018, for commercial INDs). Subsequently, in April 2017, in response to industry comments	34
and internal review, FDA extended the implementation date for drug master files (DMFs) to	35
36 months (to May 5, 2018) (revision 4), and in April 2018, FDA extended the implementation	36
date for Type III DMFs to 48 months (May 5, 2019) (revision 5). After issuing revision 5, FDA	37
determined that many of the concerns expressed in industry comments and confirmed by internal	38
review remained. Therefore, the Agency revised this guidance to further extend the	39
implementation date for Type III DMFs until May 5, 2020 (revision 6) . In February 2020, the	40
Agency issued revision 7 to include exemptions for Type III DMFs. In addition, revision 7	41
included criteria identifying the types of submissions that may qualify for a long-term or a short-	42
term waiver from eCTD submission requirements and how to submit a waiver request.	43
44
This revision (revision 8) modifies previous versions by updating hyperlinks throughout;	45
updating language to include eCTD v4.0 in sections III.F, H, J, and L; and updating eCTD v4.0-	46
related documents in section IV.	47
48
49
II. 	BACKGROUND	50
51
In section 745A(a) of the FD&C Act, Congress granted explicit authorization to FDA to	52
implement the statutory electronic submission requirements in guidance and required that FDA	53
“shall” issue such guidance. Accordingly, as indicated by the words must or required, this	54
document is not subject to the usual restrictions in FDA’s good guidance practice (GGP)	55
regulations, such as the requirement that guidances not establish legally enforceable	56
responsibilities (see 21 CFR 10.115(d); see also the guidance for industry Providing Regulatory	57
Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food,	58
Drug, and Cosmetic Act (December 2014) (the 745A(a) Implementation guidance)).	59
60
To comply with the GGP regulations and make sure that regulated entities and the public	61
understand that guidance documents are nonbinding, FDA guidances ordinarily contain standard	62
language explaining that guidance documents should be viewed only as recommendations unless	63
specific regulatory or statutory requirements are cited. FDA is not including this standard	64
language in this guidance because it is not an accurate description of all the effects of this	65
guidance. Insofar as this document specifies the format for electronic submissions or provides	66

3
“criteria for waivers of and exemptions from” the requirements of section 745A(a) of the FD&C	67
Act, it will have binding effect.	68
69
70
III. 	REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE	71
72
As of May 5, 2017, sponsors and applicants must submit the content for which an electronic	73
format for submission is specified in this guidance in such electronic format unless the	74
submission is exempted or waived. In other words, such submissions must be consistent with the	75
requirements set forth below in this section.	76
77
A. 	Types of Submissions That Must Adhere to the Electronic Submission	78
Requirement Described in This Guidance	79
80
Section 745A(a) of the FD&C Act applies to submissions under section 505(b), (i), or (j) of the	81
FD&C Act and under section 351(a) or (k) of the Public Health Service (PHS) Act. These	82
include the following submission types:	83
84
• 	Certain investigational new drug applications (INDs)7,8	
85
• 	New drug applications (NDAs)	86
• 	Abbreviated new drug applications (ANDAs)	87
• 	Certain biologics license applications (BLAs)9,10	
88
7 This guidance is not applicable to investigational new drug applications (INDs) for devices that are regulated by
CBER as biological products under section 351 of the PHS Act and that also require the submission of an IND
before the submission of a biologics license application (BLA). Although a discussion of which devices CBER
regulates as biological products is outside the scope of this guidance, as a general matter, this category of INDs
would include investigational devices that are used to screen blood donations for certain transfusion-transmissible
infections and to test human cells, tissues, or cellular or tissue-based products to make a donor-eligibility
determination. These submissions are subject to the requirements under section 745A(b) of the FD&C Act. See the
guidance for industry and FDA staff eCopy Program for Medical Device Submissions (April 2020), which
implements the electronic copy provisions of section 745A(b) for medical device submissions to FDA.
8 This guidance is not applicable to noncommercial INDs.
9 This guidance is not applicable to those devices that are regulated by CBER as biological products under section
351 of the PHS Act, including those that do not require the submission of an IND before the submission of a BLA.
Although a discussion of which devices CBER regulates as biological products under section 351 of the PHS Act is
outside the scope of this guidance, as a general matter, this category would include devices that are used to screen
blood donations for certain transfusion-transmissible infections and reagents used in determining donor/recipient
compatibility in transfusion medicine. These submissions are subject to the requirements under section 745A(b) of
the FD&C Act. See the guidance for industry and FDA staff eCopy Program for Medical Device Submissions
(April 2020).
10 Specifically, this guidance is not applicable to submissions for blood and blood components, including Source
Plasma.

4
Section 745A(a) also applies to all subsequent submissions, including amendments, supplements,	89
and reports, to the submission types identified above.11,12	
90
91
FDA considers master files to be submissions to an NDA, ANDA, BLA, or IND and therefore to	92
fall within the scope of requirements set forth in section 745A(a). These include new DMFs (21	93
CFR 314.420) and other master files relevant to a biological product (21 CFR 601.51)13 and any	94
amendments to or annual reports on previously submitted DMFs or other master files relevant to	95
a biological product. This guidance also applies to submissions for drug/device combination	96
products filed pursuant to section 505 of the FD&C Act or subsection (a) or (k) of section 351 of	97
the PHS Act.	98
99
A submission that is not in the electronic format(s) described in this guidance will not be filed or	100
received unless it has an exemption or waiver for the electronic submission requirements (see	101
sections III.C, III.D, and III.E) with respect to that submission.	102
103
Under section 745A(a)(3) of the FD&C Act, the electronic submission requirements do not apply	104
to submissions described in section 561 of the FD&C Act (e.g., expanded access INDs and	105
protocols for individual patients, including for emergency use; expanded access INDs and	106
protocols for intermediate-sized patient populations; and expanded access treatment INDs and	107
protocols). FDA will continue to accept submissions under section 561 in alternative formats	108
(e.g., portable document format (PDF) files following the common technical document (CTD)	109
organization).14	
110
111
B. 	Timetable for Implementation of Electronic Submission Requirements	112
113
The requirement to submit NDAs, ANDAs, and BLAs electronically became effective 24 months	114
after May 5, 2015 (i.e., May 5, 2017). The requirement for INDs and master files, other than	115
11 Although certain postmarketing safety report submissions fall within the scope of section 745A(a) of the FD&C
Act, FDA has separate regulations that require postmarketing safety reports to be submitted in electronic format (see
21 CFR 310.305, 314.80, 314.98. 600.80, and 600.81 and section 760 of the FD&C Act) and has issued related non-
binding guidance on these postmarketing safety reports. Accordingly, FDA has not issued guidance under section
745A with respect to electronic format for postmarketing safety reports. For recommendations with respect to
submissions related to postmarketing safety reports under §§ 310.305, 314.80, 314.98. 600.80, and 600.81 or under
section 760 of the FD&C Act, see the guidance for industry Providing Submissions in Electronic Format —
Postmarketing Safety Reports (April 2022). FDA may consider, at a future date, whether to include information in
guidance pertaining to submission of postmarketing safety reports in electronic format under section 745A(a) of the
FD&C Act.
12 For further information about IND safety reports, see 21 CFR 312.32 and the guidance for industry Safety
Reporting Requirements for INDs and BA/BE Studies (December 2012). Additional information may also be found
in the guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports (April
2024).
13 For the purposes of this guidance, the term DMF refers to both drug master files and master files relevant to
biological products.
14 See the ICH guidance for industry M4 Organization of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use (October 2017).

5
Type III DMFs, to be filed electronically became effective 36 months after May 5, 2015 (i.e.,	116
May 5, 2018). For all of these submission types, if you do not have an exemption or waiver, you	117
must electronically submit any amendments, supplements, and reports in eCTD format, even if	118
the original submission was submitted to FDA in non-eCTD format before implementation of the	119
electronic submission requirements.	120
121
The timetable for the initial implementation of the electronic submission requirement is shown in	122
italics below. Table 1 summarizes the timetable.	123
124
On May 5, 2015, FDA issued the final guidance for industry on Providing Regulatory	125
Submissions in Electronic Format — Certain Human Pharmaceutical Product	126
Applications and Related Submissions Using the eCTD Specifications. Submission types	127
NDA, ANDA, and BLA must be submitted in eCTD format beginning May 5, 2017. IND	128
submissions and master files, other than Type III DMFs, must be submitted in eCTD	129
format beginning May 5, 2018.	130
131
Table 1: Timetable for the Initial Implementation of the Electronic Submission	132
Requirement	133
134
Submission
Type
Final eCTD Guidance
Posted on FDA
Website
(yyyy-mm-dd)
Date Requirement
Begins
(yyyy-mm-dd)
NDA
ANDA
BLA
2015-05-05 	2017-05-05
Commercial IND
Master Files Other Than
Type III DMFs
2015-05-05 	2018-05-05
135
Additional information regarding submissions pertaining to promotional materials made to the	136
Office of Prescription Drug Promotion in CDER and to the Advertising and Promotional	137
Labeling Branch in CBER is described in a separate guidance, which also provides the timetable	138
for implementation of those submissions in electronic format.15	
139
140
15 See the guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic Format —
Promotional Labeling and Advertising for Human Prescription Drugs (April 2022).

6
C. 	Types of Submissions Exempted From the eCTD Requirement Described in	141
This Guidance	142
143
Section 745A(a)(2) of the FD&C Act allows FDA to establish exemptions from the electronic	144
submission requirements. Accordingly, FDA has exempted the following from the eCTD	145
requirements under section 745A(a)(2):16	
146
147
1. 	All submissions to noncommercial INDs.17 For the purposes of this guidance, the term	148
noncommercial IND refers to an IND for a product that is not intended for commercial	149
distribution; this exemption includes research and investigator-sponsored INDs.	150
151
2. 	All Type III DMF submissions.18	
152
153
Although these specific submissions will be exempt from filing in eCTD format as described in	154
this guidance, FDA still encourages applicants to send submissions in an alternative electronic	155
format (e.g., PDF files following the CTD structure).	156
157
D. 	Certain Positron Emission Tomography Drugs and Type II DMF	158
Submissions That May Qualify for a Waiver From the eCTD Requirement	159
Described in This Guidance	160
161
Section 745A(a)(2) authorizes FDA to establish criteria for waivers from its electronic	162
submission requirements. Accordingly, FDA may grant a long-term waiver from the eCTD	163
requirements under section 745A(a)(2)19 in the following circumstances:	164
165
16 See section III.B of the 745A(a) Implementation guidance (Providing Regulatory Submissions in Electronic
Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act). Noncommercial
IND submissions are not required to submit a request for this exemption.
17 Noncommercial IND submissions are not required to submit a request for this exemption. Although INDs
covered under section 561 of the FD&C Act might be referred to as a type of noncommercial IND, they have been
statutorily excepted from the scope of section 745A(a). As a result, they need not submit in eCTD format, albeit for
a different reason than the submissions exempted here. See section III.A of this guidance for information on the
types of INDs covered under section 561 of the FD&C Act.
18 Type III DMFs are submitted to the Agency to provide information regarding packaging or packaging materials in
support of NDAs, ANDAs, or BLAs. The DMF web page is accessible at
https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/drugmasterfilesdmfs/default.
htm.
19 See section III.C of the 745A(a) Implementation guidance.

7
1. 	Certain Positron Emission Tomography Drug Submissions	166
167
The requirement to comply with the eCTD requirement for certain positron emission tomography	168
(PET20) IND, NDA, ANDA, or BLA submissions could adversely impact the development and	169
availability of PET drugs. FDA may grant a waiver to a PET drug sponsor or applicant intending	170
to submit an IND, NDA, ANDA, or BLA if all of the following apply:	171
172
(a) The applicant produces PET drugs at a single PET drug facility.	173
174
(b) PET drugs are the only FDA-regulated drug products (other than noncommercial drug	175
or biological products) manufactured or produced by the sponsor or applicant.	176
177
(c) The sponsor or applicant explains that because it meets the criteria in (a) and (b)	178
above, it cannot achieve compliance with eCTD requirements.	179
180
A waiver request should be sent to FDA before submitting the document(s) for which this	181
waiver is claimed,21 with an explanation regarding why the sponsor or applicant’s	182
compliance with the requirement cannot be achieved, including that the sponsor or	183
applicant is representing that (a) through (c) above are met22 and a description of the	184
proposed alternative submission format23 the sponsor or applicant will be using during the	185
duration of the waiver (e.g., PDF files following the CTD structure).	186
187
The information provided in the waiver request may be verified through inspection or through a	188
records request in lieu of an inspection.	189
190
20 PET is a medical imaging method that produces a computerized image (scan) using a unique type of
radiopharmaceutical. A PET drug is a radioactive drug characterized by spontaneous disintegration of unstable
nuclei by the emission of positrons and is used for providing dual photon positron emission tomographic diagnostic
images (21 CFR 212.1). PET drugs are distinct among radiopharmaceuticals because of their unique production
methods, and many are characterized by their short half-lives (some as short as 20 minutes). Many PET drug
production facilities are close in proximity to the patients to whom the drugs are administered, and the production of
the drug is on demand.
21 Sponsors and applicants should request a pre-assigned application number before submitting a waiver request.
22 See section 745A(a) of FD&C Act and 21 CFR 312.10 and 314.90(a)(1).
23 If submission in eCTD format is not possible, FDA still encourages applicants to send submissions electronically
in an alternative electronic format (e.g., PDF files following the CTD structure).

8
2. 	Certain Type II DMF Submissions	191
192
Holders of certain Type II DMFs24 that solely support an application for a PET drug or a	193
noncommercial IND application may also qualify for a waiver. FDA recognizes that the holders	194
of these Type II DMFs may be distinct from the holder of the application(s) in question. FDA	195
may grant a waiver to a holder intending to submit a Type II DMF if the Type II DMF holder	196
explains that it cannot achieve compliance with eCTD requirements because one of the following	197
applies:	198
199
(a) The Type II DMF is intended to support an application for a PET drug (i.e., IND,	200
NDA, ANDA, or BLA) and contains information regarding radiolabeled drug	201
products or production of PET radionuclides, and the Type II DMF holder is an	202
academic institution, government (state or federal) entity, or a nonprofit25 research	203
organization.	204
205
OR	206
207
(b) The Type II DMF is solely used to support a noncommercial IND application, and the	208
Type II DMF holder is an academic institution, government (state or federal) entity,	209
or a nonprofit research organization.	210
211
A waiver request should be sent to FDA before submitting the document(s) for which this	212
waiver is claimed,26 with an explanation regarding why the sponsor or applicant’s	213
compliance with the eCTD requirement cannot be achieved (i.e., that the sponsor or	214
applicant is representing that (a) or (b) above is met), including a description of the	215
proposed alternative submission format27 the sponsor or applicant will be using during the	216
duration of the waiver (e.g., PDF files following the CTD structure).	217
218
The information provided on the waiver request may be verified through inspection or through a	219
records request in lieu of an inspection.	220
221
3. 	Where to Submit Waiver Requests	222
223
Waiver requests for qualifying PET drugs or Type II DMFs should be submitted in one of the	224
following ways:	225
226
24 Type II DMFs are submitted to the Agency to support drug applications to make quality information available for
Agency evaluation of the quality of active pharmaceutical ingredients and drug products used in investigational
studies.
25 For the purposes of this guidance, a nonprofit is a charitable organization recognized as tax-exempt under section
501(c)(3) of the United States Internal Revenue Code of 1986 (Title 26 of the United States Code).
26 Sponsors and applicants should request a pre-assigned application number before submitting a waiver request.
27 See footnote 25.

9
• 	CDER:	227
- 	Email to esub@fda.hhs.gov	228
229
• 	CBER	230
- 	Email to esubprep@fda.hhs.gov	231
232
The waiver request should reference all products that are to be covered by the waiver. The	233
waiver request should be clearly titled “LONG-TERM WAIVER REQUEST — eCTD	234
REQUIREMENTS” in bold capital letters at the top of the first page of the submission.	235
236
4. 	FDA Response to Waiver Requests	237
238
FDA reviews waiver requests on a case-by-case basis. 	FDA will generally respond to the	239
requestor28 in writing, stating whether the waiver is granted or denied and whether the proposed	240
alternative submission format is acceptable. Long-term waivers from the requirement to	241
submit in eCTD format, if granted, will be valid for five (5) years from the date the waiver	242
is granted, will apply only to the requestor, and will not be transferrable to another	243
sponsor or applicant. Sponsors or applicants may reapply to recertify their eligibility for this	244
waiver up to 6 months before the waiver expiration date, using the same process as described in	245
section III.D.3 of this guidance. If the criteria are no longer met at the time of recertification, the	246
waiver will not be granted.	247
248
If FDA grants a waiver, the requestor should include a statement in the cover letter of each	249
subsequent submission indicating that an eCTD submission waiver has been granted by	250
FDA, including the dates for the waiver.	251
252
Although these specific submissions may receive waivers from eCTD format requirements as	253
described in this guidance, FDA still encourages applicants to send submissions electronically in	254
an alternative electronic format (e.g., PDF files following the CTD structure).29	
255
256
E. 	Types of Submissions That May Qualify for a Short-Term Waiver From the	257
eCTD Requirement Described in This Guidance	258
259
Section 745A(a)(2) of the FD&C Act authorizes the Agency to set forth criteria for waivers from	260
the requirements of electronic submissions. FDA will grant short-term waivers from the eCTD	261
requirement only in unique and rare circumstances and for a limited duration. Companies	262
experiencing technical difficulties with transmission of their electronic submissions to FDA	263
should consult FDA for technical assistance rather than submitting a waiver request. FDA may	264
grant temporary waivers of the requirement for eCTD submission if one or more of the following	265
events or circumstances exist:	266
267
28 To follow up with the company, FDA will generally contact the individual who submitted the waiver request
unless an alternate contact person is provided.
29 See footnote 25.

10
• 	Extraordinary events or circumstances occur that are beyond the control of the submitter	268
that justify a waiver, including but not limited to, natural disasters that impact computer	269
operations.	270
271
• 	An unplanned long-term internet disruption or other unplanned event occurs that would	272
preclude the sponsor from submitting in eCTD format (e.g., malware attacks).	273
274
• 	The sponsor or applicant intends to request a withdrawal of an application that has not yet	275
converted to eCTD format.	276
277
• 	The sponsor or applicant submitted a request for withdrawal and has not yet received	278
FDA’s acknowledgement of the withdrawal.	279
280
1. 	Content of Waiver Requests	281
282
The sponsor or applicant’s request to waive the eCTD electronic format requirement must	283
include all of the following as supporting documentation to justify the waiver:30	
284
285
(a) A description of the circumstances or event — including the anticipated duration	286
of the circumstance or event — giving rise to the need for a waiver	287
288
(b) The requested duration of the waiver	289
290
(c) A description of the proposed alternative submission format31 the sponsor or	291
applicant will be using for the duration of the waiver	292
293
The request should reference all products that are to be covered by the waiver. The waiver	294
request should be clearly titled “WAIVER REQUEST — eCTD REQUIREMENTS” in bold	295
capital letters at the top of the first page of the submission.	296
297
Please submit waiver requests before filing a submission to which the waiver is claimed.	298
299
2. 	Where to Submit Waiver Requests	300
301
Waiver requests for NDAs, BLAs, ANDAs, DMFs, and commercial INDs may be sent to FDA	302
through the following means:	303
304
• 	CDER	305
- 	Email to esub@fda.hhs.gov	306
307
• 	CBER	308
- 	Email to esubprep@fda.hhs.gov	309
30 See 21 CFR 312.10(a)(3) and 314.90(a)(3).
31 See footnote 25.

11
310
3. 	FDA Response to Waiver Requests	311
312
FDA reviews waiver requests on a case-by-case basis. FDA will generally respond to the	313
requestor32 in writing, stating whether the waiver is granted or denied. If the waiver is granted,	314
FDA will also generally include in its response letter a description of the alternate submission	315
method(s) the Agency intends to accept and the time frame for the waiver. Waivers of the	316
requirement to submit in eCTD format, if granted, will be temporary, will apply only to	317
the requestor, and will not be transferrable to another sponsor. If FDA grants a waiver,	318
the requestor should include a statement in the cover letter of subsequent submissions	319
indicating that an eCTD submission waiver has been granted by FDA, including the dates	320
for the waiver.	321
322
Although these specific submissions may receive waivers from eCTD format requirements as	323
described in this guidance, FDA still encourages applicants to send submissions electronically in	324
an alternative electronic format (e.g., PDF files following the CTD structure33).	325
326
F. 	The eCTD Specifications	327
328
You must submit electronic submissions using a version of eCTD currently supported by FDA.	329
The versions of eCTD currently supported are specified in the Data Standards Catalog (available at	330
https://www.fda.gov/industry/fda-data-standards-advisory-board/study-data-standards-resources)	331
and is further described in the following technical specification documents:	332
333
International Council for Harmonisation (ICH) eCTD Version 3.2.2:	334
335
• 	ICH Electronic Common Technical Document Specification	336
337
• 	ICH eCTD Backbone File Specification for Study Tagging Files	338
339
• 	FDA eCTD Backbone Files Specification for Module 1	340
341
ICH eCTD Version 4.0:	342
343
• 	ICH eCTD v4.0 Implementation Guide	344
345
• 	FDA eCTD v4.0 Module 1 Implementation Guide	346
347
Additional technical specification documents are cited throughout this guidance. For a complete	348
list of required technical supportive files (e.g., style sheets and valid values) that you will need in	349
order to submit in the eCTD format, refer to the eCTD web page at	350
32 To follow up with the company, FDA will generally contact the individual who submitted the waiver request
unless an alternate contact person is provided.
33 See footnote 25.

12
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-	351
technical-document-ectd.	352
353
G. 	Pre-Submission Considerations	354
355
Before making the first electronic submission to an application, you must obtain a pre-assigned	356
application number by contacting the appropriate Center. Information regarding how to obtain a	357
pre-assigned application number may be found on the eCTD web page at	358
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/submit-using-ectd.	359
360
H. 	Submission Structure: Granularity, Files, and Folders	361
362
Document granularity, or the level for which the submission content is broken out into separate	363
files, must be consistent with the Granularity Document found in the ICH guidance for industry	364
M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals	365
for Human Use (October 2017) unless otherwise specified in the ICH M2 technical specification	366
eCTD IWG Question and Answer and Specification Change Request Document.	367
368
When submitting documents electronically using ICH eCTD version 3.2.2, with a few	369
exceptions, the eCTD specification maps the CTD headings to extensible markup language	370
(XML) elements.34 When submitting documents electronically using ICH eCTD version 4.0, the	371
eCTD specification maps the CTD headings to Health Level 7 (HL7) Regulated Product	372
Submission (RPS) Version 3 schema. The specification indicates that each element (heading) is	373
optional and that multiple document references (eCTD leaf or Context of Use elements) can be	374
created under each heading.	375
376
You must also follow the FDA eCTD technical specification The Comprehensive Table of	377
Contents Headings and Hierarchy for the comprehensive list of headings and hierarchy and a	378
section mapping the headings to their respective regulations.35 Because this is a comprehensive	379
list, not all headings are applicable to all submissions or submission types.	380
381
Files pertaining to each module must be placed in the appropriate folder (e.g., m1 – m5). The	382
terms folder and subfolder, as used in this guidance, are intended to be synonymous with	383
directory and subdirectory. The main submission, regional administrative folders, and certain	384
subfolders must have specific names.	385
386
You must use only letters, numbers, hyphens, or underscores in the folder and file names and not	387
blank spaces or special characters. When naming folders and files, the length of the entire path	388
must not exceed 150 characters. Empty folders and files must not be included in the submission.	389
34 For example, in Module 3, lower-level headings subordinate to 3.2.P.2 (e.g., 3.2.P.2.1, 3.2.P.2.1.1) are not
mapped to an XML element. Consequently, leaf element files relating to, for example, 3.2.P.2.1, 3.2.P.2.1.1, either
must be submitted as multiple leafs under the parent 3.2.P.2 element (heading) or combined into larger files and
submitted at the 3.2.P.2 heading level.
35 See eCTD v3.2.2 or v4.0 submission standards at https://www.fda.gov/drugs/electronic-regulatory-submission-
and-review/electronic-common-technical-document-ectd for corresponding version of The Comprehensive Table of
Contents Headings and Hierarchy for eCTD.

13
390
All documents in the electronic submission must be placed in a main submission folder and	391
named using the sequence number (which you must specify):	392
393
• 	eCTD version 3.2.2 submissions must use a 4-digit number with leading zeros.	394
• 	eCTD version 4.0 submissions must use whole numbers without leading zeros.	395
396
The eCTD backbone file for the submission must be placed in the main submission folder along	397
with the checksum file for the eCTD backbone file:	398
399
• 	The eCTD version 3.2.2 backbone file (index.xml) applies only to modules 2 through 5	400
and uses md5 checksum.	401
402
• 	The eCTD version 4.0 backbone file (submissionunit.xml) applies to all modules and	403
uses sha256 checksum.	404
405
Numbering for each subsequent submission to the same application is described in:	406
407
• 	eCTD version 3.2.2, FDA technical specification, section III.B of the eCTD Backbone	408
Files Specification for Module 1	409
410
• 	ICH eCTD version 4.0 Implementation Guide	411
412
Sequence numbers are used to differentiate between submissions within the same application and	413
need not correspond to the order in which they are received by FDA. It is not necessary for	414
sequence numbers and IND serial numbers to match for submissions to an IND.	415
416
Subfolders within each module are required to organize files in a submission. These subfolders	417
must be placed in the sequence number folder. Empty subfolders must not be included. When	418
submitting documents electronically using eCTD version 3.2.2, the util subfolder is required to	419
organize supporting eCTD technical files in the submission, as described in the ICH M2	420
technical specification Electronic Common Technical Document Specification. Other specific	421
folder names that are compliant with the eCTD version 3.2.2 format can be found in the same	422
document. When submitting documents electronically using eCTD version 4.0, the required	423
compliant subfolder names and supporting eCTD technical files are described in the ICH eCTD	424
Version 4.0 Implementation Guide.	425
426
I. 	File Formats and Versions	427
428
Files within an eCTD submission must adhere to the formats and versions specified in the	429
associated FDA technical specification Specifications for File Format Types Using eCTD	430
Specifications. PDF files submitted must adhere to the FDA technical specification Portable	431
Document Format (PDF) Specifications.	432
433

14
J. 	Document Life Cycle	434
435
If a document replaces a document previously submitted with an eCTD backbone file within the	436
same application, you must use the eCTD replace operation to indicate this, rather than	437
submitting the file as new.	438
439
When submitting documents electronically using ICH eCTD version 3.2.2, you must not indicate	440
that files are new if they are in fact replacing files already submitted. If you intend to remove a	441
file, you must use the delete operation. For instructions, see the ICH M2 technical specification	442
Electronic Common Technical Document Specification.	443
444
When submitting documents electronically using ICH eCTD version 4.0, if a document replaces	445
one or more previously submitted documents within the same application, you must use the	446
replacementOf element. You must not indicate that files are new if they are in fact replacing	447
files already submitted. If you intend to remove a file, you must use the suspended status code.	448
For instructions, see the ICH eCTD Version 4.0 Implementation Guide.	449
450
K. 	Summary of Clinical Efficacy and Summary of Clinical Safety	451
452
When submitting a Summary of Clinical Efficacy and/or a Summary of Clinical Safety, the	453
location of these documents within the eCTD must adhere to the guidance for industry Integrated	454
Summaries of Effectiveness and Safety: Location Within the Common Technical Document	455
(April 2009).	456
457
L. 	Datasets and Study Information	458
459
Datasets must only be provided in modules 3, 4, or 5 and not in modules 1 or 2.	460
461
When submitting documents electronically using ICH eCTD version 3.2.2 and providing study	462
information in either module 4 or 5, you must include the Study Tagging File (STF) described in	463
the associated ICH M2 technical specification eCTD Backbone File Specification for Study	464
Tagging Files (see section III.F above). Datasets must be referenced in an STF using the	465
appropriate STF file-tag describing the document’s contents.	466
467
When submitting documents electronically using ICH eCTD version 4.0 and providing study	468
information in either module 4 or 5, you must include the Keyword Definition for a Study Id and	469
Study Title described in the associated ICH eCTD version 4.0 Implementation Guide (see section	470
III.F above). Datasets must be referenced in the submission unit using the appropriate document	471
type keyword describing the document’s contents.	472
473
For further information regarding the submission of study data, see the guidance for industry	474
Providing Regulatory Submissions in Electronic Format — Standardized Study Data (June	475
2021).	476
477

15
M. 	Transmitting Electronic Submissions	478
479
The FDA Electronic Submissions Gateway (ESG)36 enables the secure submission of regulatory	480
information for review and is our preferred method of transmission. For all submissions that are	481
10 gigabytes (GB) or smaller, you must use the FDA ESG.	482
483
For submissions that are greater than 10 GB, refer to the FDA technical specification	484
Transmitting Electronic Submissions Using eCTD Specifications.	485
486
N. 	FDA Forms	487
488
Electronic submissions must include only FDA fillable forms (e.g., Form FDA 1571 or Form	489
FDA 356h) and electronic signatures to enable automated processing of the submission. FDA	490
forms are available at https://www.fda.gov/about-fda/reports-manuals-forms/forms. Scanned	491
images of FDA forms will not be accepted.	492
493
O. 	Restrictions on Submission of Paper Copies	494
495
When submitting in eCTD format, paper copies of the application, including review copies and	496
desk copies in paper, must not be submitted. The only exception to this is the submission of	497
paper copies of meeting briefing materials, when requested, as described in the guidances for	498
industry on formal meetings between the FDA and sponsors or applicants.37	
499
P. 	Receipt Date	500
501
The receipt date for an electronic submission will be determined only after the submission has	502
passed a technical validation check to ensure that it can be opened, processed, and archived. The	503
submitter is responsible for monitoring their receipt pathway to determine whether a submission	504
has been rejected. Additional information on the validation of electronic submissions is	505
available in the FDA technical specification Specifications for eCTD Validation Criteria.	506
507
Additional information on receipt dates for electronic submissions is available in the guidance	508
for industry Providing Regulatory Submissions in Electronic Format — Receipt Dates (February	509
2014).	510
511
Contact Information:	512
513
For questions related to providing electronic submissions according to the recommendations in	514
this guidance, contact the Electronic Submission Support Team (ESUB) at esub@fda.hhs.gov for	515
submissions to CDER and at esubprep@fda.hhs.gov for submissions to CBER. Specific	516
36 Additional information concerning the FDA ESG is available at
https://www.fda.gov/industry/electronic-submissions-gateway.
37 See also the following draft guidances: Formal Meetings Between the FDA and Sponsors or Applicants of
PDUFA Products (September 2023) and Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA
Products (August 2023). When finalized, these guidances will represent FDA’s current thinking on these topics.

16
questions pertaining to the content of applications should be directed to the appropriate review	517
division or office.	518
519
520
IV. 	TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS	521
GUIDANCE	522
523
524
The following are technical specification documents referenced in this guidance (see section I).	525
526
For a complete list of the current technical supportive files that you will need in order to submit	527
in eCTD format, refer to the eCTD Submission Standards document located on FDA’s eCTD	528
web page at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-	529
common-technical-document-ectd.	530
531
532
1. 	Electronic Common Technical Document Specification - ICH M2 technical specification	533
534
2. 	The eCTD Backbone File Specification for Study Tagging Files - ICH M2 EWG	535
technical specification	536
537
3. 	eCTD Backbone Files Specification for Module 1 - FDA technical specification	538
539
4. 	eCTD IWG Question and Answer and Specification Change Request Document - ICH	540
M2 technical specification	541
542
5. 	FDA eCTD Comprehensive Table of Contents Headings and Hierarchy - FDA	543
technical specification	544
545
6. 	Specifications for File Format Types Using eCTD Specifications - FDA technical	546
specification	547
548
7. 	Portable Document Format (PDF) Specifications - FDA technical specification	549
550
8. 	Transmitting Electronic Submissions Using eCTD Specifications - FDA technical	551
specification, Transmission Specifications	552
553
9. 	Specifications for eCTD Validation Criteria - FDA technical specification, eCTD	554
Validation Specifications web page	555
556
10. eCTD v4.0 Implementation Guide - ICH M8 technical specification	557
558
11. Module 1 eCTD v4.0 Implementation Guide - FDA technical specification	559
560

17
V. 	RELATED REFERENCES	561
562
The guidance documents referenced below can be accessed via FDA’s guidance web page at	563
https://www.fda.gov/industry/fda-basics-industry/guidances.	564
565
1. 	Providing Regulatory Submissions in Electronic Format — Submissions Under Section	566
745A(a) of the Federal Food, Drug, and Cosmetic Act (December 2014) - FDA guidance for	567
industry	568
569
2. 	Providing Regulatory Submissions in Electronic Format — Standardized Study Data (June	570
2021) - FDA guidance for industry	571
572
3. 	Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products	573
(September 2023) - FDA draft guidance for industry	574
575
4. 	Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products (August	576
2023) - FDA draft guidance for industry	577
578
5. 	Providing Submissions in Electronic Format – Postmarketing Safety Reports (April 2022) -	579
FDA guidance for industry	580
581
6. 	Providing Regulatory Submissions in Electronic Format — Receipt Dates (February 2014) -	582
FDA guidance for industry	583
584
7. 	M4 Organization of the Common Technical Document for the Registration of	585
Pharmaceuticals for Human Use (October 2017) - ICH guidance for industry	586
587
8. 	Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical	588
Document (April 2009) - FDA guidance for industry	589
590
9. 	Reporting Requirements for INDs and BA/BE Studies (December 2012) - FDA guidance for	591
industry	592
593
10. Providing Regulatory Submissions in Electronic Format: IND Safety Reports (April 2024) -	594
FDA guidance for industry	595
596
11. Providing Regulatory Submissions in Electronic and Non-Electronic Format — Promotional	597
Labeling and Advertising for Human Prescription Drugs (April 2022) - FDA guidance for	598
industry	599
600
601
602
603
604
605