Electronic Regulatory Submissions and Review

Electronic Regulatory Submissions and Review

Welcome to the Center for Drug Evaluation and Research's Electronic Regulatory Submissions and Review (ERSR) web page. This page provides information about the electronic submission of regulatory information to the Center and the review of it by CDER staff. Additional guidance documents, when available in draft or final form, will be added to this page.

Submission of Electronic Documents (6/7/2004)

Send all electronic submissions (except ANDAs) to:

5901-B Ammendale Road
Beltsville, MD 20705

Send ANDA submissions to:

7500 Standish Place, E-150
Rockville, MD 20855

CDER and the Center for Biologics Evaluation and Research (CBER), has copublished a guidance document called Guidance for Industry: Providing Regulatory Submissions in Electronic Format - General Considerations. This document provides general information about the electronic submissions process.

Note: In the general considerations guidance, we recommend the following:

"Digital Tape - Digital Equipment Corp. DLT 20/40 and 10/20 GB format using OPENVMS with VMS backup or NT server 4.0 with NT backup or backup exec."

Since the release of this guidance, there have been some changes in CDER. First, we are currently not able to accept tapes using OPENVMS with VMS backup. Second, we are able to use 35/70 DLT tapes. We are not, however, able to handle 40/80 DLT tapes. We are working on an update to this guidance and plan to add this information accordingly. (Posted 3/1/01)

Since the above posting on March 1, 2001, CDER is now able to handle 40/80 DLT tapes though we prefer 35/70. CDER cannot process DLT tapes that have been prepared using the backup applet included with the Windows 2000 operating system. It is recommended that systems running Windows 2000 use backup exec to produce the DLT transport tape for CDER. (Posted 9/28/01).

For more information on ERSR guidance documents, please contact Randy Levin, levinr@cder.fda.gov

Information on electronic datasets that accompany an ANDA submission:

You may now submit ANDAs in electronic format in place of paper. We have placed the ANDA on public docket 92S-0251 as a submission acceptable in electronic format as allowed under 21 CFR Part 11. It should be noted that Part 11 requires that datasets provided in electronic format and used in the review process meet the requirements for archiving, i.e., protection of those records to enable their accurate and ready retrieval throughout the records retention period.

Electronic datasets, including those accompanying a paper submission cannot be considered as official and used to support the application if they are submitted in a file format that is not archivable. As FDA and industry progress in meeting the goals of use of electronic submissions, compliance with electronic submission regulations will be expected. Typically, electronic datasets accompany an ANDA application to support the review of bioequivalence studies. With the implementation of the guidance for industry Providing Regulatory Submissions in Electronic Format – ANDAs (June 2002), the submission of these dataset records for use in the review should be in archivable format. At this time, the archival dataset format is SAS Transport. (Posted 7/15/2002)

We have a draft guidance for providing annual reports in electronic format. This information is described in detail in Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Annual Reports for NDAs and ANDAs. [Word] or [PDF]

See also: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions [Word] or [PDF].

Carcinogenicity Data

We have a guidance for providing carcinogenicity data in electronic format. This information is described in detail in Guidance for Industry: Providing Regulatory Submissions in Electronic Format - NDA.
An example of a SAS transport file for carcinogenicity data set is available. This is a self-extracting ZIP file that will be loaded to your C drive. If you download this file, the path to the example is: C:\WINDOWS\TEMP\example\N123456\pharmtox\datasets\101.
For more information on carcinogenicity data, please contact Karl Lin.

Digital ECG Data Submissions

As evidenced by the document The Clinical Evaluation of QT Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs

, jointly authored by U.S. and Canadian regulatory authorities, and discussed at a joint FDA/DIA meeting in January 2003, FDA is interested in reviewing ECG waveform data, obtained during the course of "definitive" studies of drug effects on ventricular repolarization, and annotated for interval measurements. A proposed format for the submission of such data was recently reviewed by HL7 (www.HL7.org) and was the subject of a request for comments published in the Federal Register (docket 03N-0158).

XMLFDA links to a company that has produced a viewer for these data files and placed this viewer in the public domain.

XMLFDA 2.0.3 (357 KB - last update July 25, 2003) XML FDA Viewer (freeware version). Requirements: Microsoft MSXML 4.0 SP1 library (or higher). Includes a PDF user manual.

Password to download EXE: amps

Send e-mail to badilini@aol.com if you need help.

eRT Data Sets (415KB)

23 ECGs in the Annotated ECG Waveform Standard. The password to the zip file is: abc.

Drug Master File (DMF)

Refer to the Draft Guidance for Industry: "Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions" [Word] or [PDF] for information on the submission of electronic DMFs.
For more information on electronic submissions for DMF, please contact CDER at esub@fda.hhs.gov. General DMF questions may be sent to Art Shaw.

Investigational New Drug Applications (INDs)

On March 26, 2002, FDA published final guidance on the submission of INDs in electronic format to the Center for Biologics Evaluation and Research (CBER) (http://www.fda.gov/cber/gdlns/eind.pdf) . Once the IND submission to CBER is posted on public docket 92S-0251, we will be capable of accepting INDs submitted to CBER in electronic format without paper copies. At this time, we are not extending this to INDs submitted to CDER.

The electronic IND guidance leverages the current BLA/NDA guidances and the experience set from CBER’s eIND pilot program. This guidance features PDF tables of contents, roadmap files, and a folder structure that enables the reviewer to easily access and review documents. We expect the experience of receiving the IND applications and amendments with or without media, featuring an electronic signature, as well as the review of these electronic INDs submissions to help the FDA further other electronic submission initiatives.

In the future, we plan on upgrading the electronic IND filing and review process to include the use of XML-based technology. We are currently working toward accepting the electronic common technical document using XML for marketing applications and will build on this to accept XML-based electronic INDs. Once this is completed, we will then issue draft guidance that incorporates the XML-based technology for all INDs including those submitted to CDER. We hope to have XML specifications for electronic INDs available in 2003.

Federal Register notice for the public meeting to discuss the cumulative table of contents for the IND. Optional format: PDF. (Posted 12/29/2000)
Agenda for the Electronic Investigational New Drug Application: Cumulative Table of Contents (CTOC) Public Meeting. (Posted 1/22/2001)
Electronic Investigational New Drug Application (IND) Cumulative Table of Contents (Posted 12/6/2000) This web page provides technical information for an upcoming public meeting to discuss the possibility of a cumulative table of contents in extensible markup language (XML) for the electronic IND.

Guidance for Industry Providing Regulatory Submissions in Electronic Format - Postmarketing Expedited Safety Reports. Optional format: PDF. This guidance document assists applicants making regulatory submissions in electronic format to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). (Issued 5/2001, Posted 5/25/2001).

Postmarketing Expedited and Periodic ICSRs This allows for voluntary electronic submission of all postmarketing individual case safety reports, whether expedited or periodic, in electronic format in place of paper

Adverse Event Reporting System. A pilot program for electronic submission of individual case safety reports is now being conducted with pharmaceutical manufacturers with approved products. The format follows the International Conference on Harmonization (ICH) standards. For more information on the ICH, please contact Timothy Mahoney at mahoneyt@cder.fda.gov.

For more information on the proposed electronic submission of individual case safety reports, see 63 FR 59746, Advanced Notice of Proposed Rulemaking (ANPRM) for Electronic Reporting of Postmarketing Adverse Drug Reactions, published on November 5, 1998.

Electronic Common Technical Document. 7/21/2004 FDA would like to work closely with people who plan to provide a submission using the eCTD specifications and offers several steps to help smooth the process.

Electronic Table of Contents Viewer (8/5/2003)

The ICH eCTD specification calls for a regional Module 1 Document Type Definition file to allow regional information to be submitted along with information from ICH Modules 2 to 5. We are using the FDA draft eCTD module 1 DTD version 2.01 (to download, right click on the link and choose "Save Target As") to gain experience on working with an electronic table of contents viewer. After downloading the file can be viewed with any text software. (Updated 8/5/2003)
The FDA draft eCTD module 1 DTD version 2.01 file is meant for informational purposes only and will likely change. The file should not be considered a component of any guidance, policy, or FDA regulation. Consult FDA regulations and guidance or send inquiries to esub@cder.fda.gov for information on submitting electronic applications to the Agency. To save this file, right-click on the link and choose "Save Target As." The file can be viewed with any text software. Please direct any comments on this file to Timothy Mahoney at mahoneyt@cder.fda.gov.
We have been working on software for reviewers to navigate electronic submissions based on the ICH eCTD. We have listed some of the general understanding we have gained to date of the useful requirements review staff may have when viewing an electronic table of contents. We think this list will change as the Agency gains more experience viewing electronic submissions. General Considerations for FDA Reviewers Viewing an Electronic Table of Contents (Posted 2/24/2003)

Patient Profile Viewer; Notice of Pilot Project. HTML or PDF Written/electronic comments by January 9, 2002.

Electronic Document Room (EDR)

The EDR is an extension of the central document room. We perform a check on each submission sent to the EDR for file formats used and integrity of bookmarks and hypertext links.
NDA Conformance Check List (2/22/2000)

Secure Electronic Mail

Although electronic mail is in widespread use within CDER and within the regulatory industry, CDER has yet to adopt formal policies for accepting regulatory submissions or formal correspondences through electronic mail. A driving factor of this has been the relative immaturity of security and encryption products that may be used efficiently in large organizations such as CDER. Because regulatory submissions include trade secrets and patient information, confidentiality of transmitted information is required.
For more information on secure electronic mail, please contact Wendy Lee at leew@cder.fda.gov.

Division Files System (DFS)

DFS is the cornerstone of the Administrative Management of Files (AMF) initiative. It provides document management, tracking, archiving, and electronic signature capabilities for internally generated review documents. It also provides search and retrieval capabilities for final versions of internally generated review documents
DFS is being developed incrementally. The first phase focuses on building an electronic repository for final review documents and for capturing signature information. The review documents tracked and saved by DFS are associated with regulatory submissions in the Centerwide Oracle Management Information System (COMIS) Future phases of DFS will include an update of COMIS assignments when the author signs the review in DFS. Reviewers use DFS to check in final review documents, to route them for sign off, to sign off on them electronically, to automatically store review documents in the electronic repository, and to find and view documents stored in the DFS electronic repository.
The DFS is a graphical user interface (GUI) software application that has the look and feel of most Windows-based applications. DFS uses standard Windows features, such as icons, drop-down menus, buttons, scroll bars, and dialog boxes.

Reviewer Training

Electronic Submissions Training (EST). Instructs reviewers on how to search for a specific NDA via the Electronic Document Room (EDR) Intranet site and to map the drive path of the folder. Acrobat Exchange is then used to open, navigate, view, follow links, create electronic notes, and copy and paste text, tables, and graphics into other applications from a sample electronic NDA.
Electronic Data Analysis Training (EDAT). Instructs reviewers on how to access NDA data in SAS Transport format via the Electronic Document Room (EDR) and to convert the files to formats that can be used with a variety of software packages. NEDAT incorporates the use of the SAS System Viewer, Stat/Transfer, and JMP to convert the data and perform basic analysis. Additional introduction to JMP courses are also available that discuss analysis of adverse events, exposure, efficacy, lab, and demographic data.
Creating Portable Document Format Reviewer Documents. Instructs reviewers on how to create a Portable Document Format (PDF) version of a review document that maintains the formatting of the original MS Word document. Instruction covers fonts, paragraph, page, and section formatting needed prior to converting an MS Word review document to the PDF archiving standard used in the Division Files System (DFS). Adobe Acrobat 4.0 is then used to convert the document to PDF and to open, view, and enhance the PDF review document.
JMP. An introduction to JMP teaches reviewers how to use JMP to review electronic data. Users learn how to use a variety of JMP functions to analyze electronic data, with a specific focus on adverse event, laboratory, exposure, and efficacy data. Basic functions of summary tables, graphs, statistical tests, and the formula calculator are covered. The course is taught in the computer lab with hands-on instruction. Prior completion of the NDA Electronic Data Analysis Training (NEDAT) course and/or familiarity with electronic datasets is recommended. Although primarily geared toward the clinical reviewer, the course provides useful instruction for reviewers of all disciplines.

Helpful Links

Docket

The Agency established the Electronic Submissions Public Docket number 92-0251 to provide a permanent location for a list of the Agency units that are prepared to receive electronic submissions, as well as a list of the specific types of regulatory records that can be accepted in electronic format (62 FR 13467, March 20, 1997).

Portable Document File (PDF) Format

PDF is an open format developed by Adobe Systems. Additional information is available at http://www.adobe.com.

SAS Transport File Format

We are able to archive data sets in SAS XPORT transport format, also called version 5 SAS transport format. This is an open, published file format developed by SAS Institute. For additional information, see the SAS Institute's Standards for Electronic Submissions and SAS XPORT transport format web site.

Technical Assistance

For more general information regarding the preparation of submissions in electronic format, please contact the Electronic Submissions Coordinator at esub@cder.fda.gov.

Recent Presentations

Electronic Submissions and Data Standards Quarterly Update, 3/4/2004, Rockville, MD, FDA
- Update on SEND (Standard for Exchange of Nonclinical Data), Thomas Papoian, Ph.D., CDER [HTML] or [PPT]
- Overview of the eCTD Guidance and Its Implementation, Gary M. Gensinger, MBA, CDER [HTML] or [PPT]
- Introduction to SDTM v3.1, Norman Stockbridge, CDER [HTML] or [PPT]

Study Tagging File Workshop [PPT slides] [HTML] Thomas Selnekovic, CDER, 2/26/2004

eCTD Workshop, February 26, 2004, Randy Levin, MD. CDER [HTML] or [PPT]

Public Meeting on Clinical Data Interchange Standard Consortium (CDISC) Version 3 Submission Data Standards and Electronic Case Report Tabulations, October 2, 2003, Rockville, Maryland. (Posted 10/7/2003)

Future of Case Report Tabulation Submissions, Randy Levin, MD,
Web Submission Data Manager (WebSDM): Demonstration, Steve Wilson, DrPH.

2003 Annual DIA Meeting, June 2003, San Antonio TX (Posted 7/15/2003)

DIA Annual Clinical Data Management Meeting in Philadelphia held on March 31, 2003.

Data Standards Update, Randy Levin, MD

DIA Electronic Document Management Meeting, February 13, 2003. (Posted 2/24/2003)

DailyMed Initiative: Enhancing Patient Safety Through Accessible Medication Information, Randy Levin, MD
FDA Data Council Initiatives, Randy Levin, MD

Electronic Submissions to the FDA, Randy Levin, MD, 5th Annual Electronic Document Management Conference, 9/23/2002. (Posted 11/14/2002)

Impact of Regulations on Data Management Practice, Randy Levin, MD, DIA 12th Annual European Clinical Data Management Conference, 11/5/2002. (Posted 11/14/2002)

Questions and Answers

We are working on consolidating some of the answers we have provided to questions on electronic submissions received in workshops and through email and will post them here when available.

Other ERSR Links

CDER Electronic Records; Electronic Signature Regulations. This page provides links to pertinent Code of Federal Regulations and Federal Register documents.
ERSR Agency Charter. Federal Register - Electronic Records; Electronic Signatures, Final Rule, March 20, 1997.

FDA/Center for Drug Evaluation and Research
Last Updated: July 22, 2004
Originator: OTCOM/DML
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