October 12, 2020

FDA Experts Provide Tips to Eliminate eCopy Holds for Premarket Submission Applications: FDA Touts eSTAR Development

Author: Suzanne Broussard, PhD 

Up to 7% of premarket submissions are placed on eCopy Hold. At a recent public workshop, FDA experts provided multiple tips to device manufacturers to avoid this trap and get their submission accepted the first time. Although the workshop focused on spinal device premarket reviews, most of the tips are relevant for all device manufacturers submitting premarket submission applications.  

Sometime in the near future, FDA will roll out this new electronic Submission Template and Resource (eSTAR) portal making eCopy obsolete. However, FDA urges manufacturers to take advantage of its current guidelines and resources to make their documents as clean as possible and ready for review right now.  

The currently used eCopy is a digital version of the traditional paper submission that reviewers interact with, like a paper copy. Failure to meet all the technical requirements of eCopy results in the eCopy Hold, which resets the review clock upon resubmission and can be costly to manufacturers.  

According to Zane Wyatt, Premarket Tools and Template Developer for FDAs Office of Regulatory Programs, the 7% of FDAs premarket submissions placed on eCopy Hold could have been avoided by taking the following steps.

1. Use the newest eCopy guidance document published April 27, 2020: 

eCopy Program for Medical Device Submissions – Guidance for Industry and Food and Drug Administration Staff 

Note that the eCopy electronic version of your medical device submission created and submitted on a CD, DVD or flash drive does not increase or decrease the type or amount of data included in a submission to support clearance or approval.  

The FDA processes the eCopy onto a secure internal database that has upload restrictions, thus the strict technical requirements. If the submission fails the technical requirement for intake and archival, the submission is placed on eCopy Hold until all the technical requirements are met that allow the reviewers access to the document. 

The eCopy guidance document provides details on: 

  • Submission types that require an eCopy 
    • Premarket notification submissions (510(k)), including third party 510(k)s
    • Evaluation of automatic class III designation petitions (de novos)
    • Premarket approval applications (PMAs), including Transitional PMAs
    • Modular PMAs 
    • Product development protocols (PDPs)
    • Investigational device exemptions (IDE) submissions 
    • Humanitarian device exemptions (HDEs) submissions 
    • Emergency Use Authorizations (EUAs) 
    • Certain investigational new drug applications (INDs)
    • Certain biologics license applications (BLAs)
    • Q-submissions
  • Other submission types not subject to the eCopy legislation for which eCopies may be submitted 
  • Processing steps for eCopy 
  • Devices regulated by CBER 
  • Technical Standards of the eCopies 
    • Document content (original, supplement, amendment, or report) 
    • Create company letter head per specific requirements 
    • Determine volume-based or non-volume-based structure 
    • Specifics on PDF requirements (naming convention, root level, Adobe Acrobat version, no embedded attachments, no security settings, size limit of 50MB) 
    • Use of non-PDFs 
    • Package preparation and mailing to the Document Control Center (CCC) 

2. Consider using the FDAs eSubmitter-eCopies Tool (voluntary) to format your eCopy content. 

The eCopy Validation tool is a downloadable software that can help compile all documents into the correct format, however, the electronic documents still need to be physically sent to the FDA document center. 

3. Use eCopy Validation on the FDA website using the most recent version (July 20, 2018). 

FDA Tip to Applicants: 
“It is recommended that you use the eCopy Validation Module to check the final eCopy on the CD, DVD, or flash drive before submitting it to the FDA in order to identify any errors or hidden files that may cause an eCopy to fail the eCopy Loader used by FDA. 

(eSTAR) – 510(k) submissions through eSTAR are currently in a pilot program. The dynamic PDF submission template will provide many advantages including: 

  • Content mirrors the reviewer’s Smart Template 
  • Integration and elimination of guidance documents 
  • Automation and Integrated Databases 
  • Guides 
  • No special software install or training 
  • Works on mobile and Macs, and is free to use 

Employing these three tips to your premarket submission could save your organization valuable time in the review process with regulatory authorities. FDA is moving towards a fully electronic submission that is dynamic, responsive, and flexible in its development of eSTAR. Until eSTAR is fully available for all premarket submissions, these tips from FDA experts may come in handy.  

Preparing all the technical documents required for premarket submission will require much more effort. 

Criterion Edge’s team of medical writers are experts at preparing the technical, safety, and regulatory documents required to get to the premarket submission phase. Feel free to reach out to us for a free consult.  

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September 22, 2020

[FEATURED] FDA Updated Its eMDR System. Here’s What You Need To Know When Submitting Adverse Events

Executive Summary

The US agency has completed planned modifications to its electronic Medical Device Reporting system – and added an extra field for MDR exemption numbers.

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July 20, 2020

[FEATURED] FDA To Makers Of EUA Devices: Don’t Forget To Report Adverse Events

Manufacturers of devices granted emergency use authorization (EUA) status during the COVID-19 crisis are fully responsible for filing any adverse events about the products to the FDA, the US agency says on a new FAQ page.

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January 14, 2020

High-level Overview of the 4 510(k) Guidance Documents for Premarket Notification by the FDA that Benefit Both FDA Reviewers and Device Sponsors

Author: Suzanne Broussard, PhD

The Premarket Notification 510(k) Program is the pathway used by manufacturers of low- to moderate-risk devices that are substantially equivalent (SE) to a device already on the market in order to begin the process of legally marketing in the United States. The Food and Drug Administration’s (FDA) release of 4 updated 510(k) guidance documents on September 13, 2019 was intended to both help streamline the FDA reviewer process and help sponsors save time and resources.  

The 510(k) Program is required for any device that does not need a Premarket Approval Application (PMA) and does not meet the specified exceptions. The sponsor must demonstrate that a device is at least as safe and effective, e.g. SE, to a legally marketed device that is not subject to PMA. The 510(k) submitters must receive a SE order from the FDA in order to market the device in the U.S. The SE determination typically takes 90 days, although that time is decreasing. Indeed, faster response times are one of FDA’s anticipated outcomes of these 4 guidance documents. The FDA hopes another outcome will be more guidance for the sponsors to streamline their submission process which will save time and resources. These outcomes are prevalent throughout the document and summarized in the FDA statement that 510(k) submissions “address the recommendations of an FDA guidance document should be easier to prepare by manufacturers and for FDA to review.” 

FDA Definition of a Legally Marketed Device 

Legally marketing a device based on a claim of substantially equivalent to devices legally marketed prior to May 28, 1976 (preamendments devices) requires the manufacturer to submit a Premarket Notification 510(k). The majority of premarket devices use the 510(k) program; hence, it is important to clarify FDA’s definition of a legally marketed device.  

A Legally Marketed Device must fit one of these 4 criteria: 

  • A Device that was legally marketed prior to May 28, 1976 (preadmendments device), or 
  • A device which has been reclassified from Class III to Class II or I 
  • A device which has been found SE through the 510(k) process 
  • A device that was granted marketing authorization via the De Novo classification process under section 513(f)(2) of the FD&C  

Note that the legally marketed device(s) used for equivalence is commonly referred to as the “predicate.”  

Here is a summary of the four 510(k) guidance documents FDA released to streamline the process and a bonus FDA webinar on Special 510(k)s. 

Refuse to Accept Policy for 510(k)s

The Refuse to Accept Policy for 510(k) Final Guidance Document contains nonbinding recommendations and supersedes the “Refuse to Accept Policy for 510(k)s” issued early in the same year (February 21, 2019). The newest Refuse to Accept (RTA) policy includes an early review that will inform the submitter within the first 15 calendar days after receipt of the 510(k) submission of issues against specific acceptance criteria with information as to the administrative completeness and if not, includes identification of missing element(s). This guidance includes checklists of which items a sponsor should include in their 510(k) submission if they want to ensure their application is reviewed in a timely fashion.  

Abbreviated 510(k) Program Final Guidance Document

The Abbreviated 510(k) Program is used by the FDA as an optional approach to the traditional 510(k) Program to demonstrate SE in premarket notifications by using guidance documents, special controls, and/or voluntary consensus standards to facilitate review of 510(k) submissions. This review relies on summary reports that “briefly describe and summarize the testing performed to support the submission as recommended in relevant guidance document(s).” 

Device manufacturers can choose the Abbreviated 510(k) pathway if the submission relies on one or more of the following: 

  • FDA guidance document 
  • Demonstration of compliance with special controls for the device type, either in a device-specific classification or a special controls guidance document; and/or 
  • Voluntary consensus standard(s) 

Format for Traditional and Abbreviated 510(k)s

The FDA provides specific guidance for the general framework of Traditional 510(k)s and Abbreviated 510(k)s in the Final Guidance Document. These formatting guidelines do not apply to Special or other premarket 510(k) submissions. FDA believes that using this Formatting Guidance will conserve both FDA and industry resources as well as facilitate timely 510(k) review. 

Special 510(k) Program

The Special 510(k) Program is designed to provide an optional and potentially expedited pathway to legally market “well-defined device modifications where a manufacturer modified its own legally marketed device and design control procedures produce reliable results that can form, in addition to other 510(k) content requirements, the basis for substantial equivalence (SE).” 

The Special 510(k) Program: Guidance for Industry and Food and Drug Administration Staff provides the FDA’s current thinking and intent on premarket notifications that are appropriate for review as a Special 510(k). This Final Guidance Document describes an optimal pathway for certain well-defined device modification for manufacturers that modify their own legally marketed device and clarifies the types of technological changes that are appropriate for review including changes to design, labeling, and indications for use. 


To further help clarify the Special 510(k) Program, the FDA recently held a webinar to discuss the Special 510(k) Program Final Guidance, and to answer questions. It is packed with useful information for those considering filing for the Special 510(k) Program including eligibility factors and examples of devices appropriate and those not appropriate for a Special 510(k). The recording of the webinar can be accessed here

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December 17, 2019

What is the Role of the Quality Overall Summary (QOS) in BLA and NDA applications?

Author: Suzanne Broussard, PhD 

The Food and Drug Administration (FDA) is promoting the Quality Overall Summary (QOS) as a powerful tool to promote effective communication between regulators and sponsors of drugs as well as a tool that can substantially impact the efficiency and quality of the regulator’s assessment. The QOS is required for all New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs) and Biologics License Applications (BLAs), thus the QOS has significant potential to impact the regulatory review process for getting marketing approval. 

The QOS summarizes all quality-related information in the application. As part of Module 2 of the electronic Common Technical Document (eCTD), the QOS links to the sponsor’s larger body of data in Module 3. The QOS is expected to provide the regulator with sufficient information to understand the contents of Module 3 in a high-level overview. However, FDA suggests that many sponsors are falling short of these expectations and are not fully utilizing this powerful tool as an effective guide for regulators to assess the application.  

In order to help sponsors prepare a QOS that facilitates the regulators’ understanding of the product’s risks as outlined in the NDA, ANDA, or BLA applications, the FDA’s Office of Pharmaceutical Quality (OPQ) published a white paper that provides practical tips for putting the quality pieces together and explaining what regulators would like to see in the QOS: A Regulators Perspective on the Quality Overall Summary: Putting the Pieces Together.

The QOS provides the sponsor with an opportunity to summarize the key aspects of the new drug or biologics application, explain specific items for the regulators to consider, and extend to post-approval comments. Yet, a poorly written QOS requires regulators to spend significant effort to “understand, summarize, collate, and interpret quality data from module 3 (Figure 1).  

Figure 1. There can be a disconnect between applicants and regulators regarding the communication of quality data and its impact on the assessment. Currently, it takes time and/or communications (e.g., information requests) to fully understand the quality of data and its significance in an application.  

The FDA’s white paper describes key considerations for creating a highquality QOS to ensure regulators have a good idea of the potential risk to the patient and the control of this risk in the commercially manufactured product. The 3 key considerations are: 

  1. Identifying the main risks to the patient from a product quality perspective. 
  2. Understanding how the proposed overall control strategy controls and/or mitigates the identified failure modes of the manufacturing process or products.
  3. Acknowledging potential considerations for the quality assessment of the submission.

These key considerations are designed to help regulators evaluate the potential risks related to quality, and their potential impact on the patients, in a summarized benefit and risk assessment. Indeed, the FDA is encouraging sponsors to explain important aspects of the new drug or biologic such as how the product was formulated, and how the risk might impact the patients. Further clarifications on the 3 key considerations are provided in the FDA’s white paper.

Writing these technical documents to concisely convey information is challenging and you might want to consider these project management and quality control tips when putting you QOS together. These tips might just help improve your QOS, which will reduce the number of information requests from the FDA and thus decrease your NDA / BLA review time.

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