How to Submit an eCTD to the FDA

11 August, 2017

drug safety.jpgTo market a drug or biological product in the United States, you must provide adequate information to the FDA demonstrating that the product is safe and effective for the conditions prescribed, recommended, or suggested in the proposed labeling for the product.

The Electronic Common Technical Document (eCTD) is the standard format for submitting applications, amendments, supplements and reports to the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER).

The eCTD format provides support for all application types including:

  • Investigational New Drug Applications (INDs)
  • New Drug Applications (NDAs)
  • Biologics License Applications (BLAs)
  • Abbreviated New Drug Applications (ANDAs)
  • Drug Master Files (DMFs)

In 2003, the FDA issued a guide that includes specifications for the eCTD. The eCTD specifications marked the start of a transition to electronic standards-based submissions.

Starting on January 1, 2008, the FDA withdrew previous eNDA and eANDA guidances, leaving eCTD as the only electronic submission format for CDER.

As of May 5, 2017 submission of NDAs, ANDAs and BLAs to the Center for Drug Evaluation and Research (CDER) using the eCTD format became mandatory. For commercial INDs and Master Files the deadline is May 5, 2018.

The FDA’s website provides a wealth of information on the submission of the eCTD including specifications and steps to follow to help simplify the process. It is recommended that before filing a submission, applicants should:

  • Review the published guidance and specifications documents provided on the eCTD website, located under the Resources tab.
  • Submit an eCTD sample prior to submitting an actual eCTD submission. While the sample submission is not considered an official submission, it is one way that the FDA offers assistance to people who plan to provide a submission using the eCTD specifications.
  • Refer to the Comprehensive Table of Contents Headings and Hierarchy on the eCTD website, a link to which is located under the Resources tab. All of the information you need to submit is covered by these headings.

TRANSMITTING A SUBMISSION

There are two ways you can electronically transmit a submission to CDER:

  • Electronic Submissions Gateway (ESG), which is the preferred method
  • Physical media, which could be a DVD/CD-ROM or USB drive

The FDA Electronic Submissions Gateway is an Agency-wide solution for accepting electronic regulatory submissions and is the required method of transmission for eCTDs 10GB or less.

The FDA ESG enables the secure submission of regulatory information and is a conduit along which submissions travel to reach their final destination. It does not open or review submissions; it automatically routes them to the proper FDA Center.

Use of a fillable form is required, and can facilitate your submissions being in reviewers’ hands in as little as 15 minutes, depending on the submissions queue. You can view and download them here.

For a successful gateway transmission, here are some recommended steps:

  1. Submit a successful test gateway submission prior to submitting via gateway
  2. Use an FDA fillable form for automatic processing
  3. Ensure that the us-regional.xml file is complete and correct, checking the date, application #, sequence #, submission type, and drug product for accuracy
  4. Choose the appropriate center: CDER or CBER

WEBTRADER

drugsafety.jpgPrior to using the ESG, a WebTrader account has to be created by the small business owner. WebTrader is a Web interface that copies and packages your submission on your desktop in a secure fashion, transmits the submission in a fully encrypted message to the FDA, and then removes any traces of its presence from your computer.

To assist you in setting up a WebTrader account, the FDA has provided a checklist.

For policy questions and to request a WebTrader account, contact esgprep@fda.hhs.gov.

For assistance with the registration or testing process, contact ESGHelpDesk@fda.hhs.gov.

SUBMITTING VIA PHYSICAL MEDIA

usbkey.jpegYou can also send your eCTD submission via physical media, such as DVD or CD, if it is greater than 10 GB. Only one electronic copy is required. The FDA recommends that a paper copy of the cover letter, including the contact information and FDA form, is included in case the media proves to be unreadable. The FDA also recommends that the data is not compressed.

For guidelines on transmitting via physical media, refer to the FDA’s transmission specification document.

For a successful physical media submission, the FDA provides several recommendations:

  1. Submit a paper copy of the cover letter, including the contact information and FDA form, in case the physical media proves to be unreadable.
  2. Send only one copy of the submission.
  3. Do a quality check of disks before submitting to avoid blank media.
  4. Do not send submissions directly to reviewers.
  5. Recognize that processing can take two to three days from submission receipt.

VALIDATING eCTD SUBMISSIONS

You invest a great deal of time in your eCTD submissions. The last thing you want to happen is for your submission to be rejected because of a technical error. The FDA recommends that certain “validation checks” be performed on submissions in order to ensure that your submission is accurate and routed in a timely mannner. Validation checks include such things as:

  • Ensuring that the application form submitted matches the application type specified in the us-regional.xml file. For example, the us-regional.xml specified application type is NDA, but the sponsor has submitted a form 1571.
  • Ensuring the consistency of the application number specified in the us-regional.xml file and application form.

Other reasons eCTD submissions get rejected include:

  • Duplicate sequence submission received.
  • The application number in the us-regional.xml and the application number on the FDA form do not match.
  • The submission was meant for CBER, but inadvertently sent to CDER.
  • There were no files/data in the folder submitted.
  • The files submitted were corrupted and/or physical media were broken and could not be read.
  • There was no us-regional.xml file or index.xml file provided with the submission.

SUBMITTING AN eCTD SAMPLE 

Submitting a sample eCTD ahead of the actual eCTD is a very effective way of ensuring that your eCTD will be accepted. While it does not involve any FDA review of the submission content, it is very effective at resolving technical issues.

In order to submit a sample eCTD you have to obtain a sample application number from the Electronic Submissions Team at esub-testing@fda.hhs.gov, which you should only use for the sample and not for your actual eCTD submission. Once you’ve submitted your request and your contact information, a representative from the Electronic Submissions Capability Team will contact you and assign a Sample Application Number, along with additional instructions.

Next, submit your sample submission (via physical media) according to the provided instructions. The Electronic Submissions Capability Team will process your sample submission and validate that it conforms to FDA guidance and specifications. eCTD validation tests include, but are not limited to, DTD validation, verification of file checksums, verification of the presence of the modified file, and identification of missing files. When testing is complete, you will be provided with feedback, highlighting the errors found during the processing of the sample submission.

Following FDA feedback, review and resolve any technical issues that they have identified before making an actual submission to the FDA.

You may have to wait up to 30 days to receive feedback on your sample, but in most cases you can expect an answer sooner than that. After you have received and implemented the feedback, you should be technically ready to submit to the Agency in eCTD format.

REQUESTING A PRE-ASSIGNED APPLICATION NUMBER

Prior to submitting an application to CDER in eCTD format, you will need to request a pre-assigned application number. A pre-assigned application number is a unique six-digit number, e.g., 012345, assigned to sponsors to enable them to identify their application. The FDA requires that you use this number any time you submit an eCTD application.

Before you request a pre-assigned eCTD application number, you need to apply for a secure email address with the FDA by contacting SecureEmail@fda.hhs.gov.

Once you’ve obtained your secure email address you can email the FDA with your request for a pre-assigned application number. The email should be sent to: cderappnumrequest@fda.hhs.gov.

For instructions on what to include in the email visit this webpage:

How to obtain a pre-assigned application number.

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About the Author

Stephen Joseph is Vice President of Market Development at ShareVault where he oversees market development in the Life Sciences arena. Over the course of his career as a technology company founder, CEO and business executive, Steve has worked in a variety of roles helping young companies prepare for investment. He has also helped growth companies rebuild their organizations, redefine or focus business strategy, establish and improve strategic relationships, establish repeatable business processes and metrics, and set up strong smooth-functioning teams.

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