Providing Regulatory Submissions in Alternate Electronic Format 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) July 2021 Electronic Submissions Providing Regulatory Submissions in Alternate Electronic Format 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) July 2021 Electronic Submissions Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. HOW TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE ................... 2 A. How to Submit in Alternate Electronic Format (without XML backbone) ............................. 2 B. FDA Forms ..................................................................................................................................... 3 C. Pre-Submission Considerations .................................................................................................... 4 D. Submission Structure: Granularity, Files, and Folders ............................................................ 4 E. File Formats and Versions ............................................................................................................ 4 F. Datasets and Study Information ................................................................................................... 5 G. Transmitting Electronic Submissions .......................................................................................... 5 H. Receipt Dates .................................................................................................................................. 5 IV. FDA TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS GUIDANCE ................................................................................................................................... 6 V. RELATED REFERENCES ............................................................................................. 6 Contains Nonbinding Recommendations Providing Regulatory Submissions in Alternate Electronic Format Guidance for Industry 1 This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. I. INTRODUCTION This guidance provides recommendations on an alternate electronic format for submissions covered under an exemption from or a waiver of the requirements of section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 379k-1). These recommendations pertain to the format of content contained in new drug applications (NDAs), abbreviated new drug applications (ANDAs), certain drug master files (DMFs), certain biologics license applications (BLAs), and certain investigational new drug applications (INDs) submitted to the Center for Drug Evaluation and Research (CDER) or to the Center for Biologics Evaluation and Research (CBER). 2 Sponsors and applicants who receive an exemption or a waiver from filing in electronic common technical document (eCTD) format under section 745A(a) of the FD&C Act should still provide those exempted or waived submissions electronically. This recommendation is consistent with the efforts of Federal Agencies to transition their business processes and recordkeeping to a fully electronic environment. 3 The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA guidance documents, including this guidance, should be viewed only as recommendations, 1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration. 2 For more information on types of submissions covered under an exemption from or a waiver of the requirements of section 745A(a) of the FD&C Act, refer to the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020) available on the FDA eCTD website at https://www.fda.gov/ectd. 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. 3 See https://www.archives.gov/records-mgmt/memos/ac22-2019. 1 Contains Nonbinding Recommendations unless specific regulatory or statutory requirements are cited. The use of the word should in FDA guidances means that something is suggested or recommended, but not required. II. BACKGROUND In section 745A(a) of the FD&C Act, Congress granted FDA the authority to implement the Agency’s statutory electronic submission requirements in guidance. In response to this authorization, FDA implemented binding guidance requiring submission of NDAs, BLAs, ANDAs, DMFs, and commercial INDs to the Agency in eCTD format. Recognizing that certain types of submissions are exempt from this requirement and that waivers of the requirement may be granted on a case-by-case basis, the Agency is issuing this guidance to describe the alternate electronic format companies should use for submissions covered under such exemptions and waivers. III. HOW TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE A. How to Submit in Alternate Electronic Format (without XML backbone) Although the alternate electronic format utilizes the same folder structure found in eCTD submissions, it does not include XML and other specific files needed for electronic display. The alternate electronic format does not require specialized software. Commercial off-the-shelf software or other methods may be used to either build or view the submission; but like eCTD, the alternate electronic format should follow the FDA technical specification The Comprehensive Table of Contents Headings and Hierarchy. 4 For information on file format and versions, see section III.E of this guidance. Main Submission Folder All documents and data files should be placed in a main folder (top-level) using the application type and number (e.g., IND123456) as the folder name. A table of contents with hyperlinks and bookmarks should be provided in numerical order in the sequence folder (e.g., 0001) for ease of navigation to all the files contained in the submission. The alternate electronic format should follow the eCTD Technical Conformance Guide (e.g., Section 3.1.2 Cover Letter and Reviewers Guide). 5 Folders Inside the sequence folder, there should be five or fewer folders, depending on the documents being submitted: m1, m2, m3, m4, and m5. The documents should be organized and placed in 4 The Comprehensive Table of Contents Headings and Hierarchy may be found in the eCTD Submissions Standards document, available on the FDA eCTD website at https://www.fda.gov/ectd. 5 The eCTD Technical Conformance Guide is available on the FDA eCTD website at https://www.fda.gov/ectd. 2 Contains Nonbinding Recommendations their respective modules, folders, or subfolders as displayed in the FDA technical specification The Comprehensive Table of Contents Headings and Hierarchy. Each item has an assigned module and subfolder where document and data files that belong to the item should be placed. Files pertaining to each module should be placed in the appropriate folder (e.g., m1 through 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 should have specific names. Table 1 shows the organization of modules and their descriptions. Table 1. Module and Description Organization Module Description 1 Administrative Information 2 Summaries 3 Quality 4 Nonclinical Information 5 Clinical Information Folder Organization For recommendations on how to organize submission content, refer to the eCTD Technical Conformance Guide. 6 The majority of information in the eCTD Technical Conformance Guide is applicable to eCTD and non-eCTD submissions. B. FDA Forms Electronic submissions should include only FDA fillable forms (e.g., 1571, 356h, 2252) and electronic signatures to enable automated processing of the submission. FDA forms are available 6 Ibid. 3 Contains Nonbinding Recommendations at https://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm. Scanned images of FDA forms should not be submitted. 7 C. Pre-Submission Considerations Before making the first alternate electronic submission, a pre-assigned application number should be obtained by contacting CDER or CBER. For more information on obtaining a pre- assigned application number, see FDA’s eCTD web page at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/submit-using-ectd. D. Submission Structure: Granularity, Files, and Folders The level at which the submission content is broken out into separate files should be consistent with the International Council for Harmonisation (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 guidance for industry M2: eCTD Specification Questions & Answers and Change Requests (March 2005). The FDA technical specification The Comprehensive Table of Contents Headings and Hierarchy should be followed for the comprehensive listing of headings and hierarchy and for section mapping the headings to their respective regulations. Given that this technical specification includes a comprehensive listing, not all headings are applicable to all submissions or submission types. Letters, numbers, hyphens, and underscores may be used in the folder and file names, but you should not use blank spaces or special characters. When naming folders and files, the length of the path should not exceed 150 characters. Empty folders and files should not be included in the submission. Sequence numbers are used to differentiate 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 used to organize files in a submission. These subfolders should be placed in the sequence number folder. E. File Formats and Versions Files within an alternate electronic submission should adhere to the formats and versions specified in the associated FDA technical specification Specifications for File Format Types Using eCTD Specifications. PDF files should adhere to the FDA technical specification Portable Document Format (PDF) Specifications. 7 If it is not possible to provide an electronic signature to the form, submitting a signed and scanned copy of the fillable form is acceptable. An unsigned electronic version of the fillable form should be included with such submission so the data can be processed by FDA systems. 4 Contains Nonbinding Recommendations F. Datasets and Study Information Datasets should only be provided in modules 3, 4, or 5, and not in modules 1 or 2. For further information on the submission of study data, see the guidance for industry Providing Regulatory Submissions in Electronic Format — Standardized Study Data (December 2014). G. Transmitting Electronic Submissions The FDA Electronic Submissions Gateway (ESG) 8 enables the secure submission of regulatory information for review. For all submissions in alternate electronic format that are 10 gigabytes (GB) or smaller, the FDA ESG should be used. For submissions that are greater than 10 GB, refer to the FDA technical specification Transmitting Electronic Submissions using eCTD Specifications. H. Receipt Dates The receipt date for an electronic submission is established tentatively when the submission arrives through the ESG and then permanently when the submission is determined to be technically acceptable, in that it can be opened, processed, and archived. FDA will notify submitters regarding any technical deficiencies as they are encountered. However, each submitter is responsible for monitoring their receipt pathway to determine whether a submission has been rejected. 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, contact the appropriate electronic submission coordinator: CDER submissions: esub@fda.hhs.gov CBER submissions: esubprep@fda.hhs.gov Specific questions pertaining to the content of applications should be directed to the appropriate review division or office. 8 Additional information concerning the FDA ESG is available at https://www.fda.gov/industry/electronic- submissions-gateway. 5 Contains Nonbinding Recommendations IV. FDA TECHNICAL SPECIFICATION DOCUMENTS REFERENCED IN THIS GUIDANCE The following is a list of FDA technical specification documents referenced in this guidance: 1. The Comprehensive Table of Contents Headings and Hierarchy 2. eCTD Technical Conformance Guide 3. Specifications for File Format Types Using eCTD Specifications 4. Portable Document Format (PDF) Specifications 5. Transmitting Electronic Submissions Using eCTD Specifications 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. V. RELATED REFERENCES The guidance documents referenced below can be accessed via FDA’s guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 9 1. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 2020) 2. 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) 3. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format — Standardized Study Data (December 2014) 4. FDA draft guidance for industry, Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (December 2017) 5. FDA draft guidance for industry, Formal Meetings Between the FDA and Sponsors or Applicants of BSUFA Products (June 2018) 6. FDA draft guidance for industry, Providing Submissions in Electronic Format — Postmarketing Safety Reports (June 2014) 9 Note: Draft guidances are not considered FDA’s current thinking until finalized. 6 Contains Nonbinding Recommendations 7. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format — Receipt Dates (February 2014) 8. ICH guidance for industry, M2: eCTD Specification Questions & Answers and Change Requests (March 2005) 9. ICH guidance for industry, M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (October 2017) 10. FDA guidance for industry, Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document (April 2009) 7