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Fixing Q-Submission Errors that Prevent FDA Acceptance of Medical Device Submissions

You are initiating the journey of submitting your Medical Device Application to the FDA and want feedback from the agency on your planned application. How do you communicate your questions related to your planned application to the FDA? The answer to that question resides with the agency’s pre-submission program for medical devices, the Q-Submission (Q-Sub) Program.

What is the FDA Q-Sub Program?

The Q-Sub Program refers to the FDA’s tracking system for sponsors requesting feedback from or a meeting with regulators regarding potential or planned medical device applications. These applications include but are not limited to:

  • Investigational Device Exemption (IDE)
  • Premarket Approval (PMA)
  • Premarket Notification Submissions (510(k)
  • Clinical Laboratory Improvement Amendments (CLIA) Waiver by Applications (CW)
  • Investigational New Drug Applications (INDs) and Biologics License Applications (BLAs) submitted to the Center for Biologics Evaluation and Research (CBER) for devices that are regulated as biological products under section 351 of the Public Health Service (PHS) Act

The program, established in 1995 as The Pre-IDE Program, initially intended to enable sponsors a process to obtain FDA feedback on future IDE applications prior to their submission. The program evolved to include feedback on various applications, as well as to address whether a clinical study requires submission of an IDE. The Pre-Submission (Pre-Sub) Guidance, published in 2014, implemented the broader Q-Sub Program, which includes Pre-Subs and additional opportunities to engage with FDA.

What types of Q-Subs are available?

A few types of Q-Subs covered by the program include but are not limited to:

  • Pre-Subs: Formal written requests from a sponsor for FDA feedback provided in the form of a formal written response or, if the sponsor chooses, followed by a meeting in which any additional feedback or clarifications are documented in meeting minutes.
  • Other Q-Sub Types or Interactions Outside the Scope of The Q-Sub Program:
    • PMA Day 100 Meetings
    • Submissions associated with the Breakthrough Devices Program
    • Teleconferences or emails discussing general FDA policy, procedures, or simple review clarification questions
    • Requests for clarification on device-specific guidance documents or voluntary consensus standards that are not related to a specific device in development.
  • Informational Meetings:
    • Request to share information with the FDA without expecting feedback
    • Document FDA and sponsor interactions that don’t fall within the definition of other types of Q-Subs

I determined which Q-Sub type I want to submit, what now?

Overlooking common submission preparation errors can cause failure of the Q-Sub to load to FDA’s repository or an eCopy Hold (when your “eCopy”— an electronic version of your medical device submission created and submitted on a CD, DVD, or flash drive— fails intake into the FDA internal databases). Let’s look at some common Q-Sub errors and how to avoid them.

PDF Creation

PDFs are the main file type in a Q-Sub. When creating your PDFs:

  • Convert the file from its original format (i.e., Microsoft Word) using Adobe Acrobat PDF Version 11 or below, rather than creating them as scanned versions of the printed files. If you’re using Adobe Acrobat version 11 or greater, save the PDF as a reduced size PDF.
  • Don’t embed attachments.
    • Not compatible with FDA’s repository
    • Can result in information being missed during review.
    • Content isn’t searchable
    • Attachment is removed when the PDF is downloaded from the repository.
  • Don’t apply security that:
    • Allows opening of the file but prevents content modification
    • Requires passwords to open the file.

The FDA allows PDFs with this type of security. However, the agency discourages the submission of files with any type of security as it affects their ability to efficiently redact Confidential Commercial Information (CCI; any information which is not in the public domain where disclosure may undermine the legitimate economic interest of the applicant).

File Size

Individual files must be 50MB or smaller. Additionally, the FDA recommends that the total Q-Sub size be less than 1GB. Submissions over 1GB may experience delays due to the additional time needed for them to be loaded into and accessed in FDA’s repository. File Sizes can be reduced by:

  • Splitting the original file into parts
  • Compressing the file
  • Lowering the resolution to 72dpi
  • Submitting only necessary photos or portions of videos
  • Breaking down the information into several different folders inside the MISC FILES or STATISTICAL DATA folders
  • Placing larger files onto multiple CDs or DVDs

File and Folder Naming

Determining File and Folder Names prior to establishing inter-document links will ensure all links function in your final submission.

Submission Structure and Folder Naming

Determine how you want your submission to be organized (non-volume or volume based) and what files you want the FDA to see at the root (main) level when they open the CD, DVD, or flash drive.

  • Non-volume based: Recommended for small submissions and includes one or more PDFs at the root level.
  • Volume-based: Recommended for large or complex submissions. This structure includes volumes or folders at the root level which include one or more PDF files. Only PDFs can be placed in these volumes. When organizing a submission in this type of structure:
    • Establish the volume naming convention per the examples given below. This assures the FDA’s repository can create the folder sort order. Without this sort order, the volumes will load in alphabetical order.
      • VOL_xxx_Descriptive Name
      • VOL_xxx
    • Ensure the volume numbering has non-repeating, consecutive prefixes. The first volume should have a prefix of VOL_001, the second volume VOL_002, and so forth.
    • A Descriptive Name included in the volume naming should:
      • Indicate the volume’s content and be meaningful to the reviewer.
      • Not exceed 125 characters
      • Not contain any of the invalid characters noted in the eCopy Guidance or any non-English letters.
    • Avoid placing any subfolders under a volume. Even if you have non-PDF documents that are associated with a particular volume, you cannot embed the “MISC FILES” or “STATISTICAL DATA” folders within one of these volumes.

PDF File Naming Convention

Each PDF File Name must begin with a 3-digit prefix followed by an underscore (“_”) and then a Descriptive Name (e.g., 001_Cover Letter, 002_MDUFA Form). The 3-digit prefix is only used to load the PDFs into FDA’s repository in the order which they should be read. Otherwise, the loading software will load the PDFs alphabetically. If you have utilized a volume-based structure, the numbering of the PDFs within each volume will need to start over at 001_, 002_, etc.

Adding Non-PDFs

When adding Non-PDF files to your submission:

  • Add a “STATISTICAL DATA” or “MISC FILES” folder to the root level. These folders must be spelled precisely but aren’t case sensitive.
  • “STATISTICAL DATA” Folder:
    • Used to add statistical information, including metadata, data line listings and program codes, in their native formats, such as, but not limited to: SAS; XPORT; XML; SGML; S-Plus; R files; ASCII; Molfiles; and Excel.
    • Metadata includes data dictionaries and terminologies, formats, annotated case report forms, statistical analysis details, and any other information that contributes to understanding and using the data.
    • There are no restrictions on the format used; however, file formats that include variable labels and dictionary information (such as SAS XPORT) are encouraged.
  • “MISC FILES” Folder:
    • Used to add file types that cannot or should not be submitted in PDF format and are not statistical in nature (e.g., videos, x-rays, machine readable software source code). These files may be included in their native formats, such as, but not limited to: .gif; .tif; .jpg; .avi; .mpeg; .wmv; and .txt. There aren’t restrictions on the native format.
    • The FDA encourages you to also include Microsoft Word versions of certain documents or pieces of information that were also provided in the main body as PDFs in this folder. This action streamlines the FDA review process. Microsoft Word versions must not be submitted in lieu of PDF versions. Use a file naming convention similar to the PDF so that reviewers can easily make the correlation.
  • Zip all non-PDF content into one or more zip file(s). There are no limitations/restrictions on the naming convention for a zip file(s) or any of the content that you add to the zip file(s). In addition, there is no size limit for a zip file. But large files take longer to load to FDA’s repository and may present viewing issues for review staff. Therefore, the FDA strongly recommends that you take any appropriate and feasible steps to reduce the file sizes.

How do I prepare my FDA Q-Sub Submission?

Now that you have ensured that the compilation of your Q-Sub is free of the common errors, a few final steps remain to prepare your Q-Sub for Submission:

  • Validate the Submission via FDA’s eCopies Validation Module or other Validation program
  • Organize the Submission using FDA’s eSubmitter tool before transferring the Q-Sub to CD, DVD, USB
    • The Q-Sub content is saved in a folder with a long alpha-numeric name. You need to open up the folder with the long alpha-numeric name that was saved on your local computer drive and burn those contents onto your CD, DVD, or flash drive
  • Prepare your package to the CDRH DCC or CBER.
    • CDRH DCC: The package includes: (1) your Submission burned to a CD, DVD, or flash drive with a paper copy of your signed company cover letter
    • CBER: The package can be transmitted via the Electronic Submissions Gateway.

Conclusion

By ensuring your Q-Sub is organized appropriately and free of the common errors, you can:

  • Reduce the time needed to compile and submit your Submission to FDA
  • Advance the timeline of your Medical Device application
  • Minimize any load failures to FDA’s repository and eCopy Holds

We can help prepare your Q-Sub! Read more about how our Consulting, Software, and Service offerings can add value to your Q-Sub and support your company and submission goals.

References

Center for Devices and Radiological Health. eCopy program for medical device submissions. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/how-study-and-market-your-device/ecopy-program-medical-device-submissions. Published August 25, 2022. Accessed September 9, 2022.

Center for Devices and Radiological Health. Feedback and meetings for device submissions: The Q-submission program. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program. Published January 2021. Accessed September 9, 2022.

Webinar – Q-submission program for medical device submissions. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/workshops-conferences-medical-devices/webinar-q-submission-program-medical-device-submissions-june-11-2019-06112019-06112019. Published June 11, 2019. Accessed September 9, 2022.

About the author

Bethany Williams
By: Bethany Williams

Bethany Williams has been an Associate Principal Regulatory Operations Specialist at Certara since 2017. Her background consists of authoring documents used in a Quality Control environment and ensuring CMC documentation included in submissions conforms to current FDA guidances. In her current role, she leads Regulatory Operations activities for multiple applications to multiple Health Authorities.