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) 
 
 
 
 
February 2020 
Electronic Submissions 
Revision 7 
 
   
 
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., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
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)  
 
February 2020 
Electronic Submissions 
Revision 7 
   
 
RELATED DOCUMENTS 
 
Technical specifications associated with this guidance are provided as separate documents 
and are updated periodically.  Documents cited within this guidance are provided at the 
end of this document. 
 
For a complete listing of all documents and supportive files needed to submit electronically, 
refer to the eCTD web page at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
ronicSubmissions/ucm153574.htm. 
 
REVISION HISTORY 
 
DATE  SUMMARY OF REVISIONS 
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 
April 2017 
 
  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 
 
 
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 
April 2018 
(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 
 
 
   
 
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  
January 2019 
 
  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 
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 
July 2019   
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  
 
   
   
 
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 .................................. 5 
C.  Types of Submissions Exempted From the eCTD Requirement Described in This Guidance6 
D.  Certain Positron Emission Tomography (PET) 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 (PET) 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.................................................................................................................... 13 
K.   Summary of Clinical Efficacy and Summary of Clinical Safety .............................................. 13 
L.  Datasets and Study Information ................................................................................................. 13 
M.  Transmitting Electronic Submissions ........................................................................................ 14 
N.  FDA Forms ................................................................................................................................... 14 
O.  Restrictions on Submission of Paper Copies ............................................................................. 14 
P.   Receipt Date .................................................................................................................................. 14 
IV.  TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS 
GUIDANCE ................................................................................................................................. 16 
V.  RELATED REFERENCES ........................................................................................... 17 
   
 
 
Providing Regulatory Submissions in Electronic Format  Certain 
Human Pharmaceutical Product1 Applications and Related 
Submissions Using the eCTD Specifications  
Guidance for Industry2 
 
 
I.  INTRODUCTION  
 
Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 
24 months after the issuance of a final guidance document in which the Food and Drug 
Administration (FDA or Agency) has specified the electronic format for submitting submission 
types to the Agency, such content must be submitted electronically and in the format specified by 
FDA.3,4  This guidance describes how sponsors and applicants must organize the content that 
they submit to the Agency electronically for all submission types under section 745A(a) of the 
FD&C Act.  This guidance also references several technical specification documents5 and the 
Electronic Common Technical Document Conformance (eCTD) Guide, which provide additional 
details regarding the organization of content for electronic submissions.6  
 
                                                 
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 drugs approved under the FD&C Act and 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 379k1. 
 
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/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/u
cm153574.htm. 
 
6 For the most recent version of the eCTD Technical Conformance Guide, check the eCTD Resources web page at 
https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm5
35180.htm.  
 
  1 
   
 
 
This guidance implements the electronic submission requirements of section 745A(a) of the 
FD&C Act for the electronic format of the content submitted in new drug applications (NDAs), 
abbreviated new drug applications (ANDAs), certain biologics license applications (BLAs), and 
certain investigational new drug applications (INDs) to the Center for Drug Evaluation and 
Research (CDER) or the Center for Biologics Evaluation and Research (CBER).  See section 
III.A of this guidance for more information regarding required submission types.  Submissions 
that are not submitted electronically and electronic submissions that are not in a format that FDA 
can process, review, and archive will not be filed or received unless they have an exemption or 
waiver from the electronic submission requirements. 
 
 
The revised guidance published on May 5, 2015, provided a timetable of 24 months after 
issuance of the final guidance for the initial implementation of the electronic submission 
requirement for NDAs, ANDAs, BLAs, and master files (May 5, 2017) and 36 months for 
commercial INDs (May 5, 2018).  The timetable indicated that NDAs, BLAs, ANDAs, and 
master files were to be submitted electronically in eCTD format starting on May 5, 2017 (May 5, 
2018, for commercial INDs).  Subsequently, in April 2017, in response to industry comments 
and internal review, FDA extended the implementation date for drug master files (DMFs) to 
36 months (to May 5, 2018) (Revision 4) and in April 2018, FDA extended the implementation 
date for Type III DMFs to 48 months (May 5, 2019) (Revision 5).  After publication of Revision 
5, FDA determined that many of the concerns expressed in industry comments and confirmed by 
internal review remained.  Therefore, the Agency issued a revision to this guidance to further 
extend the implementation date for Type III DMFs until May 5, 2020 (Revision 6). 
 
This revision to the guidance (Revision 7) modifies previous versions by including exemptions 
for Type III DMFs (see section III.C).  In addition, this guidance has been updated to include the 
criteria identifying those types of submissions that may qualify for a long-term waiver (see 
section III.D) or a short-term waiver (see section III.E) from eCTD submission requirements and 
also includes instructions on how to submit a waiver request.  
 
 
II.  BACKGROUND 
 
In section 745A(a) of the FD&C Act, Congress granted explicit authorization to FDA to 
implement the statutory electronic submission requirements in guidance and required that FDA 
shall issue such guidance.  Accordingly, as indicated by the words must or required, this 
document is not subject to the usual restrictions in FDAs good guidance practice (GGP) 
regulations, such as the requirement that guidances not establish legally enforceable 
responsibilities (see 21 CFR 10.115(d); see also 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) (the 745A(a) Implementation Guidance)). 
 
To comply with the GGP regulations and make sure that regulated entities and the public 
understand that guidance documents are nonbinding, FDA guidances ordinarily contain standard 
language explaining that guidance documents should be viewed only as recommendations unless 
specific regulatory or statutory requirements are cited.  FDA is not including this standard 
  2 
   
 
 
language in this guidance because it is not an accurate description of all the effects of this 
guidance.  Insofar as this document specifies the format for electronic submissions or provides 
criteria for waivers of and exemptions from the requirements of section 745A(a) of the FD&C 
Act, it will have binding effect.  
 
 
III.  REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE 
 
As of May 5, 2017, sponsors and applicants must submit the content for which an electronic 
format for submission is specified in this guidance in such electronic format unless the 
submission is exempted or waived.  In other words, such submissions must be consistent with the 
requirements set forth below. 
 
A.  Types of Submissions That Must Adhere to the Electronic Submission 
Requirement Described in This Guidance 
 
Section 745A(a) of the FD&C Act applies to submissions under section 505(b), (i), or (j) of the 
FD&C Act and under section 351(a) or (k) of the Public Health Service (PHS) Act.  These 
include the following submission types: 
 
  Certain investigational new drug applications (INDs)7,8 
  New drug applications (NDAs) 
  Abbreviated new drug applications (ANDAs) 
  Certain biologics license applications (BLAs)9,10 
                                                 
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 (December 2015), 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. 
 
10 Specifically, this guidance is not applicable to submissions for blood and blood components, including Source 
Plasma. 
 
  3 
   
 
 
 
Section 745A(a) also applies to all subsequent submissions, including amendments, supplements, 
and reports, to the submission types identified above.11,12 
 
FDA considers master files to be submissions to an NDA, ANDA, BLA, or IND, and therefore to 
fall within the scope of requirements set forth in section 745A(a).  These include new DMFs (21 
CFR 314.420) and other master files relevant to a biological product (21 CFR 601.51)13 and any 
amendments to or annual reports on previously submitted DMFs or other master files relevant to 
a biological product.  This guidance also applies to submissions for drug/device combination 
products filed pursuant to section 505 of the FD&C Act or subsection (a) or (k) of section 351 of 
the PHS Act. 
 
A submission that is not in the electronic format(s) described in this guidance will not be filed or 
received unless it has an exemption or waiver for the electronic submission requirements (see 
sections III.C., III.D., and III.E.) with respect to that submission. 
 
Under section 745A(a)(3) of the FD&C Act, the electronic submission requirements do not apply 
to submissions described in section 561 of the FD&C Act (e.g., expanded access INDs and 
protocols for individual patients, including for emergency use; expanded access INDs and 
protocols for intermediate-sized patient populations; and expanded access treatment INDs and 
protocols).  FDA will continue to accept submissions under section 561 in alternative formats 
(e.g., PDF files following the common technical document (CTD) organization).14 
 
                                                 
 
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, 600.81, or section 
760 of the FD&C Act, see the draft guidance for industry Providing Submissions in Electronic Format  
Postmarketing Safety Reports (June 2014).  When finalized, this guidance will represent the FDAs current thinking 
on this topic.  FDA may consider, at a future date, whether to include information pertaining to submission of 
postmarketing safety reports in electronic format in guidance 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 draft guidance for industry Providing Regulatory Submissions in Electronic Format:  IND Safety Reports 
(October 2019).  When finalized, this guidance will represent the FDAs current thinking on this topic.  
 
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).    
 
  4 
   
 
 
B.  Timetable for Implementation of Electronic Submission Requirements 
 
The requirement to submit NDAs, ANDAs, and BLAs electronically became effective 24 months 
after May 5, 2015 (i.e., May 5, 2017), the original date of finalization of this guidance 
(Revision 3).  The requirement for INDs and master files, other than Type III DMFs, to be filed 
electronically became effective 36 months after May 5, 2015 (i.e., May 5, 2018).  For all of these 
submission types, if you do not have an exemption or waiver, you must electronically submit any 
amendments, supplements, and reports in eCTD format, even if the original submission was 
submitted to FDA in non-eCTD format before implementation of the electronic submission 
requirements. 
 
The timetable for the initial implementation of the electronic submission requirement is shown in 
italics below.  Table 1 summarizes the timetable. 
 
On May 5, 2015, FDA issued the final guidance for industry on Providing Regulatory 
Submissions in Electronic Format  Certain Human Pharmaceutical Product 
Applications and Related Submissions Using the eCTD Specifications.  Submission types 
NDA, ANDA, and BLA must be submitted in eCTD format beginning May 5, 2017.  IND 
submissions and master files, other than Type III DMFs, must be submitted in eCTD 
format beginning May 5, 2018.   
 
Table 1:  Timetable for the Initial Implementation of the Electronic Submission 
Requirement 
 
Submission  Final eCTD Guidance  Date Requirement 
Type  Posted on FDA  Begins 
Website   
(yyyy-mm-dd)  (yyyy-mm-dd) 
NDA 
ANDA  2015-05-05  2017-05-05 
BLA 
Commercial IND  
Master Files Other Than  2015-05-05  2018-05-05 
Type III DMFs 
 
Additional information regarding submissions pertaining to promotional materials made to the 
Office of Prescription Drug Promotion in CDER and to the Advertising and Promotional 
Labeling Branch in CBER is described in a separate guidance.  Refer to that guidance for the 
timetable for implementation of those submissions in electronic format.15 
 
                                                 
15 See the guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic Format  
Promotional Labeling and Advertising for Human Prescription Drugs (June 2019).     
 
  5 
   
 
 
C.  Types of Submissions Exempted From the eCTD Requirement Described in 
This Guidance 
 
Section 745A(a)(2) of the FD&C Act allows FDA to establish exemptions from the electronic 
submission requirements.  Accordingly, FDA has exempted the following from the eCTD 
requirements under section 745A(a)(2):16   
 
1.  All submissions to noncommercial INDs.17  For the purposes of this guidance, the term 
noncommercial IND refers to an IND for a product that is not intended for commercial 
distribution; this exemption includes research and investigator-sponsored INDs.  
 
2.  All Type III DMF submissions.18  
 
Although these specific submissions will be exempt from filing in eCTD format as described in 
this guidance, FDA still encourages applicants to send submissions in an alternative electronic 
format (e.g., PDF files following the CTD structure).   
 
D.  Certain Positron Emission Tomography (PET) Drugs and Type II DMF 
Submissions That May Qualify for a Waiver From the eCTD Requirement 
Described in This Guidance 
 
Section 745A(a)(2) authorizes FDA to establish criteria for waivers from its electronic 
submission requirements.  Accordingly, FDA may grant a long-term waiver from the eCTD 
requirements under section 745A(a)(2)19 in the following circumstances: 
   
                                                 
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. 
 
 
  6 
   
 
 
1.  Certain Positron Emission Tomography (PET)20 Drug Submissions 
 
The requirement to comply with the eCTD requirement for certain PET IND, NDA, ANDA, or 
BLA submissions could adversely impact the development and availability of PET drugs.  FDA 
may grant a waiver to a PET drug sponsor or applicant intending to submit an IND, NDA, 
ANDA, or BLA if all of the following apply: 
 
(a) The applicant produces PET drugs at a single PET drug facility. 
 
(b) PET drugs are the only FDA-regulated drug products (other than noncommercial drug 
or biologic products) manufactured or produced by the sponsor or applicant. 
 
(c) The sponsor or applicant explains that, because it meets the criteria above, it cannot 
achieve compliance with eCTD requirements. 
 
A waiver request should be sent to FDA before submitting the document(s) for which this 
waiver is claimed,21 with an explanation regarding why the sponsor or applicants 
compliance with the requirement cannot be achieved, including that the sponsor or 
applicant is representing that (a) through (c) above are met22 and a description of the 
proposed alternative submission format23 the sponsor or applicant will be using during the 
duration of the waiver (e.g., PDF files following the CTD structure).  
  
The information provided in the waiver request may be verified through inspection or through a 
records request in lieu of an inspection.   
 
                                                 
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).      
 
  
 
  7 
   
 
 
2.  Certain Type II DMF24 Submissions 
 
Holders of certain Type II DMFs that solely support an application for a PET drug or a 
noncommercial IND application may also qualify for a waiver.  FDA recognizes that the holders 
of these Type II DMFs may be distinct from the holder of the application(s) in question.  FDA 
may grant a waiver to a holder intending to submit a Type II DMF if the Type II DMF holder 
explains that it cannot achieve compliance with eCTD requirements because one of the following 
applies: 
 
(a) The Type II DMF is intended to support an application for a PET drug (i.e., IND, 
NDA, ANDA, or BLA) and contains information regarding radiolabeled drug 
products or production of PET radionuclides, and the Type II DMF holder is an 
academic institution, government (state or federal) entity, or a non-profit25 research 
organization. 
 
OR 
 
(b) The Type II DMF is solely used to support a noncommercial IND application, and the 
Type II DMF holder is an academic institution, government (state or federal) entity, 
or a non-profit research organization. 
 
A waiver request should be sent to FDA before submitting the document(s) for which this 
waiver is claimed,26 with an explanation regarding why the sponsor or applicants 
compliance with the eCTD requirement cannot be achieved (i.e., that the sponsor or 
applicant is representing that (a) or (b) above is met), including a description of the 
proposed alternative submission format27 the sponsor or applicant will be using during the 
duration of the waiver (e.g., PDF files following the CTD structure).  
 
The information provided on the waiver request may be verified through inspection or through a 
records request in lieu of an inspection.   
 
3.  Where to Submit Waiver Requests 
 
The waiver requests for qualifying PET drugs or Type II DMFs should be submitted in one of 
the following ways: 
                                                 
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 non-profit 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 23.  
  
  8 
   
 
 
 
  CDER:  
  Email to esub@fda.hhs.gov  
-
 
  CBER  
  Email to esubprep@cber.fda.gov 
-
 
The waiver request should reference all products that are to be covered by the waiver.  The 
waiver request should be clearly titled LONG-TERM WAIVER REQUEST  eCTD 
REQUIREMENTS in bold capital letters at the top of the first page of the submission. 
 
4.  FDA Response to Waiver Requests 
 
FDA reviews waiver requests on a case-by-case basis.    FDA will generally respond to the 
requestor28 in writing, stating whether the waiver is granted or denied and whether the proposed 
alternative submission format is acceptable.  Long-term waivers from the requirement to 
submit in eCTD format, if granted, will be valid for five (5) years from the date the waiver 
is granted, will apply only to the requestor, and will not be transferrable to another 
sponsor or applicant.  Sponsors or applicants may reapply to recertify their eligibility for this 
waiver up to 6 months before the waiver expiration date, using the same process as described in 
section III.D.3 of this guidance.  If the criteria are no longer met at the time of recertification, the 
waiver will not be granted. 
 
If FDA grants a waiver, the requestor should include a statement in the cover letter of each 
subsequent submission(s) indicating that an eCTD submission waiver has been granted by 
FDA, including the dates for the waiver.  
 
Although these specific submissions may receive waivers from eCTD format requirements as 
described in this guidance, FDA still encourages applicants to send submissions electronically in 
an alternative electronic format (e.g., PDF files following the CTD structure).29   
 
E.  Types of Submissions That May Qualify for a Short-Term Waiver From the 
eCTD Requirement Described in This Guidance  
 
Section 745A(a)(2) of the FD&C Act authorizes the Agency to set forth criteria for waivers from 
the requirements of electronic submissions.  FDA will grant short-term waivers from the eCTD 
requirement only in unique and rare circumstances and for a limited duration.  Companies 
experiencing technical difficulties with transmission of their electronic submissions to FDA 
should consult FDA for technical assistance rather than submitting a waiver request.  FDA may 
                                                 
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 23.   
  9 
   
 
 
grant temporary waivers of the requirement for eCTD submission if one or more of the following 
events or circumstances exist:    
 
  Extraordinary events or circumstances occur that are beyond the control of the submitter 
that justify a waiver, including but not limited to, natural disasters that impact computer 
operations. 
 
  An unplanned long-term internet disruption or other unplanned event occurs that would 
preclude the sponsor from submitting in eCTD format (e.g., malware attacks). 
 
  The sponsor or applicant intends to request a withdrawal of an application that has not yet 
converted to eCTD format. 
 
  The sponsor or applicant submitted a request for withdrawal and has not yet received 
FDAs acknowledgement of the withdrawal. 
 
1.  Content of Waiver Requests 
 
The sponsor or applicants request to waive the eCTD electronic format requirement must 
include all of the following as supporting documentation to justify the waiver:30 
 
(a) A description of the circumstances or event  including the anticipated duration 
of the circumstance or event  giving rise to the need for a waiver 
 
(b) The requested duration of the waiver 
 
(c) A description of the proposed alternative submission format31 the sponsor or 
applicant will be using for the duration of the waiver 
 
The request should reference all products that are to be covered by the waiver.  The waiver 
request should be clearly titled WAIVER REQUEST  eCTD REQUIREMENTS in bold 
capital letters at the top of the first page of the submission. 
 
Please submit waiver requests before filing a submission to which the waiver is claimed.   
 
2.  Where to Submit Waiver Requests 
 
Waiver requests for NDAs, BLAs, ANDAs, DMFs, and commercial INDs may be sent to FDA 
through the following means: 
 
                                                 
30 See 21 CFR 312.10(a)(3) and 314.90(a)(3). 
 
31 See footnote 23. 
  
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  CDER 
  Email to esub@fda.hhs.gov  
-
 
  CBER  
  Email to esubprep@cber.fda.gov 
-
  
3.  FDA Response to Waiver Requests 
 
FDA reviews waiver requests on a case-by-case basis.  FDA will generally respond to the 
requestor32 in writing, stating whether the waiver is granted or denied.  If the waiver is granted, 
FDA will also generally include in its response letter a description of the alternate submission 
method(s) the Agency intends to accept and the time frame for the waiver.  Waivers of the 
requirement to submit in eCTD format, if granted, will be temporary, will apply only to 
the requestor, and will not be transferrable to another sponsor.  If FDA grants a waiver, 
the requestor should include a statement in the cover letter of subsequent submission(s) 
indicating that an eCTD submission waiver has been granted by FDA, including the dates 
for the waiver.  
 
Although these specific submissions may receive waivers from eCTD format requirements as 
described in this guidance, FDA still encourages applicants to send submissions electronically in 
an alternative electronic format (e.g., PDF files following the CTD structure33).   
 
F.  The eCTD Specifications 
 
You must submit electronic submissions using the version of eCTD currently supported by FDA.  
The version of eCTD currently supported is specified in the Data Standards Catalog (available at 
https://www.fda.gov/media/85137/download) and is further described in the following technical 
specification documents: 
 
  International Council for Harmonisation (ICH) Electronic Common Technical Document 
Specification  
 
  ICH eCTD Backbone File Specification for Study Tagging Files 
 
  FDA eCTD Backbone Files Specification for Module 1 
 
Additional technical specification documents are cited throughout this document.  For a 
complete listing of required technical supportive files (e.g., style sheets and valid values) that 
you will need to submit in the eCTD format, refer to the eCTD web page at 
                                                 
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 23. 
 
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https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
ronicSubmissions/ucm153574.htm. 
 
G.  Pre-Submission Considerations 
 
Before making the first electronic submission to an application, you must obtain a pre-assigned 
application number by contacting the appropriate Center.  Information regarding how to obtain a 
pre-assigned application number may be found on the eCTD web page at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
ronicSubmissions/ucm153574.htm. 
 
H.  Submission Structure:  Granularity, Files, and Folders 
 
Document granularity, or the level for which the submission content is broken out into separate 
files, must be consistent with the Granularity Document found in the ICH guidance for industry 
M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals 
for Human Use (October 2017) unless otherwise specified in the ICH M2 technical specification 
eCTD IWG Question and Answer and Specification Change Request Document. 
 
With a few exceptions, the eCTD specification maps CTD headings to extensible markup 
language (XML) elements.34  The specification indicates that each element (heading) is optional 
and that multiple document references (eCTD leaf elements) can be created under each heading. 
 
You must also follow the FDA eCTD technical specification The Comprehensive Table of 
Contents Headings and Hierarchy for the comprehensive listing of headings and hierarchy and a 
section mapping the headings to their respective regulations.35  Because this is a comprehensive 
listing, not all headings are applicable to all submissions or submission types. 
 
Files pertaining to each module must be placed in the appropriate folder (e.g., m1  m5).  The 
terms folder and subfolder, as used in this guidance, are intended to be synonymous with 
directory and subdirectory.  The main submission, regional administrative folders, and certain 
subfolders must have specific names. 
 
You must use only letters, numbers, hyphens, or underscores in the folder and file names and not 
blank spaces or special characters.  When naming folders and files, the length of the entire path 
must not exceed 150 characters.  Empty folders and files must not be included in the submission. 
 
All documents in the electronic submission must be placed in a main submission folder and 
named using a four-digit sequence number (which you must specify) that is unique within the 
                                                 
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 https://www.fda.gov/media/76444/download. 
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application.  The eCTD backbone file for modules 2 to 5 (index.xml) for the submission must 
be placed in this folder along with the checksum file for the eCTD backbone file (index-
md5.txt). 
 
Numbering for each subsequent submission to the same application is described in the FDA 
technical specification in section III.B of the eCTD Backbone Files Specification for Module 1.  
Sequence numbers are used to differentiate between submissions within the same application and 
need not correspond to the order in which they are received by FDA.  It is not necessary for 
sequence numbers and IND serial numbers to match for submissions to an IND. 
 
Subfolders within each module are required to organize files in a submission.  These subfolders 
must be placed in the sequence number folder.  Empty subfolders must not be included.  The util 
subfolder is required to organize supporting eCTD technical files in the submission, as described 
in the ICH M2 technical specification Electronic Common Technical Document Specification.    
Other specific folder names that are compliant with the eCTD version 3.2.2 format can be found 
in the same document. 
 
I.   File Formats and Versions 
 
Files within an eCTD submission must adhere to the formats and versions specified in the 
associated FDA technical specification Specifications for File Format Types Using eCTD 
Specifications.  Portable Document Format (PDF) files submitted must adhere to the FDA 
technical specification Portable Document Format (PDF) Specifications. 
 
J.  Document Life Cycle 
 
If a document replaces a document previously submitted with an eCTD backbone file within the 
same application, you must use the eCTD replace operation to indicate this, rather than 
submitting the file as new.  You must not indicate that files are new if they are in fact replacing 
files already submitted.  If you intend to remove a file, you must use the delete operation.  For 
instructions, see the ICH M2 technical specification Electronic Common Technical Document 
Specification. 
 
K.   Summary of Clinical Efficacy and Summary of Clinical Safety 
 
When submitting a Summary of Clinical Efficacy and/or a Summary of Clinical Safety, the 
location of these documents within the eCTD must adhere to the guidance for industry Integrated 
Summaries of Effectiveness and Safety:  Location Within the Common Technical Document 
(April 2009). 
 
L.  Datasets and Study Information 
 
Datasets must only be provided in modules 3, 4, or 5 and not in modules 1 or 2.  When providing 
study information in either module 4 or 5, you must include the Study Tagging File (STF) 
described in the associated ICH M2 technical specification eCTD Backbone File Specification 
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for Study Tagging Files (see section III.F of this guidance).  Datasets must be referenced in an 
STF using the appropriate STF file-tag describing the documents contents. 
 
For further information regarding the submission of study data, see the guidance for industry 
Providing Regulatory Submissions in Electronic Format  Standardized Study Data (December 
2014). 
 
M.  Transmitting Electronic Submissions 
 
The FDA Electronic Submissions Gateway (ESG)36 enables the secure submission of regulatory 
information for review and is our preferred method of transmission.  For all submissions that are 
10 gigabytes (GB) or smaller, you must use the FDA ESG. 
 
For submissions that are greater than 10 GB, refer to the FDA technical specification 
Transmitting Electronic Submissions Using eCTD Specifications. 
 
N.  FDA Forms 
 
Electronic submissions must include only FDA fillable forms (e.g., Form FDA 1571 or Form 
FDA 356h) and electronic signatures to enable automated processing of the submission.  FDA 
forms are available at 
https://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm.  Scanned images of 
FDA forms will not be accepted. 
 
O.  Restrictions on Submission of Paper Copies 
 
When submitting in eCTD format, paper copies of the application, including review copies and 
desk copies in paper, must not be submitted.  The only exception to this is the submission of 
paper copies of meeting briefing materials, when requested, as described in the guidances for 
industry on formal meetings between the FDA and sponsors or applicants.37 
P.   Receipt Date 
 
The receipt date for an electronic submission will be determined only after the submission has 
passed a technical validation check to ensure that it can be opened, processed, and archived.  The 
submitter is responsible for monitoring their receipt pathway to determine whether a submission 
has been rejected.  Additional information on the validation of electronic submissions is 
available in the FDA technical specification Specifications for eCTD Validation Criteria. 
 
                                                 
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 (December 2017) and Formal Meetings Between the FDA and Sponsors or Applicants of BSUFA 
Products (June 2018).  When finalized, these guidances will represent FDAs current thinking on these topics. 
  14 
   
 
 
Additional information on receipt dates for electronic submissions is available in the guidance 
for industry Providing Regulatory Submissions in Electronic Format  Receipt Dates (February 
2014). 
 
 
Contact Information 
 
For questions related to providing electronic submissions according to the recommendations in 
this guidance, you should contact the Center electronic submission coordinator at 
esub@fda.hhs.gov for submissions to CDER and at esubprep@fda.hhs.gov for submissions to 
CBER.  Specific questions pertaining to the content of applications should be directed to the 
appropriate review division or office. 
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IV.  TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS 
GUIDANCE 
 
 
The following are technical specification documents referenced in this guidance (see section I).  
Documents are listed in order of first appearance in this guidance. 
 
For a complete listing of the current technical supportive files that you will need in order to 
submit in eCTD format, refer to the eCTD Submission Standards document located on the 
eCTD web page at https://www.fda.gov/ectd. 
 
 
1.  ICH M2 technical specification, Electronic Common Technical Document Specification  
 
2.  ICH M2 technical specification, The eCTD Backbone File Specification for Study 
Tagging Files  
 
3.  FDA technical specification, eCTD Backbone Files Specification for Module 1  
 
4.  ICH M2 technical specification, eCTD IWG Question and Answer and Specification 
Change Request Document  
 
5.  FDA technical specification, FDA eCTD Comprehensive Table of Contents Headings 
and Hierarchy  
 
6.  FDA technical specification, Specifications for File Format Types Using eCTD 
Specifications  
 
7.  FDA technical specification, Portable Document Format (PDF) Specifications  
 
8.  FDA technical specification, Transmission Specifications, Transmitting Electronic 
Submissions Using eCTD Specifications 
  
9.  FDA technical specification, eCTD Validation Specifications web page, Specifications 
for eCTD Validation Criteria  
 
 
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V.  RELATED REFERENCES 
 
The guidance documents referenced below can be accessed via FDAs guidance web page at 
https://www.fda.gov/industry/fda-basics-industry/guidances.  
 
1.  FDA guidance for industry Providing Regulatory Submissions in Electronic Format 
 Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act 
(December 2014)  
 
2.  FDA guidance for industry Providing Regulatory Submissions in Electronic Format 
 Standardized Study Data (December 2014) 
 
3.  FDA draft guidance for industry Formal Meetings Between the FDA and Sponsors or 
Applicants of PDUFA Products (December 2017) 
 
4.  FDA draft guidance for industry Formal Meetings Between the FDA and Sponsors or 
Applicants of BSUFA Products (June 2018) 
 
5.  FDA draft guidance for industry Providing Submissions in Electronic Format  
Postmarketing Safety Reports (June 2014) 
 
6.  FDA guidance for industry Providing Regulatory Submissions in Electronic Format 
 Receipt Dates (February 2014) 
 
7.  ICH guidance for industry M4 Organization of the Common Technical Document for 
the Registration of Pharmaceuticals for Human Use (October 2017) 
 
8.  FDA guidance for industry Integrated Summaries of Effectiveness and Safety: 
Location Within the Common Technical Document (April 2009) 
 
9.  FDA guidance for industry Reporting Requirements for INDs and BA/BE Studies 
(December 2012). 
 
10. FDA draft guidance for industry Providing Regulatory Submissions in Electronic 
Format: IND Safety Reports (October 2019). 
 
11. FDA draft guidance for industry Providing Regulatory Submissions in Electronic and 
Non-Electronic Format  Promotional Labeling and Advertising for Human 
Prescription Drugs (June 2019).     
 
 
 
 
 
 
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