Regulatory Blog Post #2 - Providing Regulatory Submissions in Electronic Format (General Considerations)

Laura Salomon
September 19, 2010

Name of Guidance:
Guidance for Industry: Providing Regulatory Submissions in Electronic Format – General Considerations

Status of Guidance/Release Date:
Providing Regulatory Submissions in Electronic Format – General Considerations is a draft guidance. It was first issued in January, 1999 and revised in October, 2003.

Link to the Guidance:
The guidance can be found at the following location:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124751.pdf

Target Audience:
General Considerations is one guidance in a series that the FDA is developing for sponsors to reference when submitting electronic applications. The target audience, therefore, includes the sponsor and any employees involved in formatting, assembling, and/or submitting electronic documents, as well as any who ensure regulatory compliance of these electronic submissions.

Laws and Regulations Referenced:
62 FR 13430 Federal Register of March 20, 1997
21 CFR, Part 11 Electronic Records; Electronic Signatures – Scope and Application

Summary:
One of the main goals of the updated draft of General Considerations is to incorporate electronic submission information in all centers of the FDA, including

• CBER – Center for Biologics Evaluation and Research
• CDER – Center for Drug Evaluation and Research
• CDRH – Center for Devices and Radiological Health
• CFSAN – Center for Food Safety and Applied Nutrition, and
• CVM – Center for Veterinary Medicine.

Additional changes from the previous draft include a description relating electronic submissions to the Code of Federal Regulations (21, part 11) and recommendations for formatting PDF documents with specific font types. Finally, the latest version of the guidance introduces new file formats such as XML (extensible markup language) and SGML (standard generalized markup language).

Electronic Submissions and the Relationship to 21 CFR Part 11
Following suit of the March 20, 1997 Federal Register, which allowed sponsors to submit records in electronic format without accompanying paper copies, CDER and CBER finalized a joint guidance document on general considerations for electronic submissions in January, 1999. The revised draft results from a working group with CBER, CDER, CDRH, CVM, and CFSAN, which formed to coordinate electronic submissions across all FDA centers. The goal of electronic submission standards complies with Section 11.2(b) of 21 CFR, which states that records submitted to the Agency may be electronic as long as the Agency is technologically able to accept them (as identified in public docket No. 92S-0251).

The guidances on electronic submissions describe general characteristics of electronic documents from the user’s perspective; based on these characteristics, PDF is the accepted format, and the user should be able to view a legible copy of the information, print specific pages of each document while maintaining its integrity (font, page orientation, etc.), navigate through the submission using a table of contents, and copy text, images, and data to other common software formats.

General Considerations also discusses detailed specifications for electronic documents, including acceptable PDF versions, fonts, page orientations and margins, hypertext linking and bookmarks, naming conventions, and several other technical standards.

File Formats for Datasets and Electronic Submission Procedures
While the original guidance document described datasets in SAS System XPORT transport format (Version 5 SAS transport file) as acceptable, the updated draft includes information on XML and SGML. XML files are read by internet browsers through use of style sheets. They form a dynamic hierarchical structure as individual files (elements) are related to one another. The FDA currently uses XML version 1.0, which is recommended by the World Wide Web Consortium (W3C). SGML, also developed by W3C, is similar to XML and has many similar features. It was developed to organize and transmit information in digital format.

The FDA has identified three methods for sending electronic submissions: via electronic data interchange (EDI), through web-based transmission, and by secure email. Additional information is provided for various transmission methods depending on specific submission types. For example, electronic submissions can also be provided on physical media formats such as floppy disks, CD-ROM, and digital linear tape.

Rationale:
An update to the original General Considerations document was required to provide information on font specifications and new acceptable file types, which was not included in January, 1999 draft. Furthermore, aligning with the Agency’s goal to address electronic submissions to all centers in one common document, this updated draft includes information on submitting to CHRH, CVM, and CFSAM, as well as CDER and CBER. As submissions are increasingly transitioning from paper to electronic, it benefits the Agency to have one document that sponsors can reference for specifications for any center or submission type.

Resulting Recommendations:
The Agency recommends that sponsors adhere to the guidance to ensure general compliance of their electronic submissions with established regulations and technical standards. General Considerations should be referenced for electronic submissions to any center in the Agency.

Impact:
The transition from paper to electronic submissions has had a major impact in industry. In general, electronic submissions are both created and reviewed faster, since large documents no longer require printing, binding, and boxing. In particular, eCTD (electronic common technical document) structures are becoming the standard, and they allow for document reuse; this structure makes the submission and review process more efficient. Considering what it takes to send hundreds of volumes of a large NDA on a truck to FDA headquarters, electronic submissions save money, space, and manual labor.

The Agency’s series of guidances on electronic submissions is impactful because industry can refer to a single group of documents for all processes and specifications that characterize this submission format. Particularly important are the updates to this draft of General Considerations, because sponsors now have information regarding submissions to any of the Agency’s centers. The FDA’s goal of increased efficiency in the review process has coincided with movement toward standardization. These standard procedures have helped to clarify the electronic submission process for all involved.