March 7, 2023
Obtaining FDA clearance or approval for your medical device may feel like a convoluted labyrinth with a path that is changing and ends in complex rejections, but FDA has a valuable tool for traversing the intricate process and aligning with the Agency prior to submitting your US premarket submission. Originally evolving from the pre-IDE program intended to provide Sponsors with feedback prior to future IDE applications, FDA’s Pre-Submission Program has evolved to include other submission types, such as PMAs, De Novo requests, 510(k)s, and HDEs. The expanded Pre-Submission Guidance was originally published in 2014 and the program has been gaining popularity as it creates a smoother application process for both FDA and Submitters.
The Pre-Submission is the ideal method to allow Sponsors to present premarket submission issues, build a working relationship with FDA at a crucial phase in their strategic development, and potentially save themselves time and money. The program is a practical way to guide Sponsors towards the most appropriate approval path for their medical device. Submitting a Pre-Submission can help Sponsors identify potential complications that may arise when seeking FDA approval or clearance for devices that don’t fit into an established regulatory route or may require complex nonclinical or clinical studies.
Depending on your device type, FDA has various premarket submission pathways that can quickly become complicated. However, Sponsors may benefit from early engagement with FDA expert reviewers. Whether you’re a first-time Submitter looking for more transparency in the premarket submission process or a seasoned medical device founder navigating the complex approval process for an innovative AI technology, the Pre-Submission program presents a constructive approach for your team to engage with FDA and increase your chances of successful clearance or approval.
What is a Pre-Submission?
Pre-Submissions are formal written requests submitted by Sponsors to FDA for written feedback with an optional in-person or virtual meeting to discuss the feedback and any necessary clarifications. Commonly referred to as Pre-Subs, a type of Q-Submission, they are optional submissions and are not required to obtain FDA clearance or approval but are encouraged by FDA, who state that the “careful consideration of FDA’s feedback may improve the quality of subsequent submissions, shorten total review times, and facilitate the development process for new devices.” Early interactions with FDA via Pre-Subs can lay the groundwork for a more transparent review process and create a strong rapport for companies who are new to the FDA submission process.
With Pre-Submissions, Sponsors can either request just a written response or a written response followed by a meeting to discuss the written feedback. Pre-Subs provide Submitters with the opportunity to familiarize FDA with their medical device, request feedback on proposed study protocols (clinical and non-clinical), and ask specific questions about their testing methods and regulatory strategy.
Pre-Submissions are submitted to FDA prior to a premarket submission to align with the Agency on what information will be required in the premarket submission. These premarket submissions can be for medical devices, in-vitro diagnostic products (IVDs), biologics or combination products. Common types of premarket submissions include:
De Novo Classification Requests – Evaluation of Automatic Class III Designations
IDE – Investigational Device Exemptions
PMA – Premarket Approval Applications
510(k) – Premarket Notifications
HDE – Humanitarian Device Exemptions
Who Should Submit a Pre-Submission?
Medical device companies that are new to the FDA submission process and looking for feedback on the regulatory requirements related to premarket submissions (510(k), De Novo, PMA) are highly encouraged to submit Pre-Submissions. Although preparing Pre-Subs involves a monetary investment and time commitment, there is no FDA review fee, unlike premarket approval submissions, and the early feedback can be invaluable, especially in cases where a device isn’t comparable to anything on the market (De Novo). De Novo Pre-Subs can be mutually beneficial, since Submitters can familiarize FDA with the new technology, which will streamline future submissions and identify any potential issues early on.
For founders that are in the process of fundraising, Pre-Submissions can also be a great tool for demonstrating value and traction to investors. Pre-Subs reviewed by FDA prior to significant premarket submissions can give investors additional confidence in your regulatory strategy and readiness. Pre-Subs can also provide a more definitive risk classification for devices whose device classification isn’t completely clear based on the regulations. This can aptly guide subsequent product development and testing, ensuring a more focused, streamline premarket submission.
What is Included in a Pre-Submission?
According to the current FDA Guidance Document, Pre-Subs should contain a cover letter, all relevant device information, and the Submitter’s specific questions along with copies of any relevant or cited publications.
Cover Letters should contain:
The Q number ID for any similar or related Q-Subs
Summaries of any previous communications with FDA about the subject device or a similar device and explanations of how the feedback has been addressed in the present submission
Note: Not all issues brought up by FDA must be addressed, but the rationale for taking a new approach or leaving feedback unresolved should be addressed.
Complete contact information of the Submitter and any consultant(s)
Q-Sub type – in this case, a Pre-Submission
Meeting election (if you choose to have one)
Include a draft agenda, the desired meeting format (in-person or teleconference), potential meeting dates and times, and details of all attendees (titles, positions, affiliations, etc.) or the type of subject matter experts you plan to invite if you have not yet finalized attendees.
Requested FDA staff in attendance
Identify and justify any appropriate FDA staff you would like present and the specific expertise needed at the meeting.
The remainder of the Pre-Sub should clearly identify the following device information:
Detail your goals with this submission and the desired outcome from FDA interactions.
All relevant information pertaining to, but not limited to, its functions, basic scientific concepts, any significant physical, performance, and technological characteristics, pertinent software used, planned testing strategy, generic, proprietary, and trademark name(s), images and videos, as needed, and a brief description of the manufacturing process if it may affect the device’s safety or efficacy.
Proposed Indications or Intended Use
Description of disease(s) or condition(s) the device is intended to diagnose, treat, prevent, cure, or mitigate and the intended patient population
Ensure sufficient and pertinent information is included based on the questions you are asking
Include all the necessary information and media necessary to explain the thought process behind the device and its use
Note: While considered safe to include more information, make sure it remains organized and easy to follow.
Any relevant previous FDA communications (submission ID) and a brief summary of the feedback and its resolution or the justification of alternate paths
Planned Follow-Up Submission
Indicate the type of future premarket submission (PMA, De Novo, 510(k), IDE) you are targeting in the Pre-Sub
Specific Questions and Topics
Submitters can request feedback on activities relevant to device studies, testing, protocols, data review, approval strategies, future development and submission preparations, etc., while making sure to include perspective and rationale .
Cite any relevant guidance, standards, and previous FDA feedback in the rationale
When asking questions, it is recommended to provide your plan and justifications for your plan, prior to asking the Agency’s opinion. It is not recommended to openly ask a question without first providing your opinion on how the issue would be handled.
What Makes for a Successful Pre-Submission Meeting?
Submitters who opt for a meeting to discuss their written feedback can expect an open conversation about their medical device’s technical, scientific, and regulatory information to ensure it aligns with FDA’s current standards for clinical, non-clinical, or analytical studies related to marketing submissions. Ahead of the meeting, Submitters should supply FDA with their presentation slides, an agenda, a list of their attendees, and requests for any specific FDA staff. Meetings are limited to an hour, so preparedness is of utmost importance for an efficient meeting.
Submitters attending in-person meetings should plan to specify any necessary AV equipment (external equipment prohibited), whether internet access will be needed, and if any visitors are non-US citizens to ensure sufficient time for the additional screening process. In-person meetings may be more challenging to schedule, but Submitters with devices that would benefit from demonstrations may prefer them.
Leverage your resources and include outside resources (e.g., Physicians, Primary Investigators from clinical studies, statisticians, NIH grant reviewers) that will help maintain transparency amongst stakeholders and increase the effectiveness of your real-time discussions with FDA.
Don’t underestimate the value of your meeting minute-taker. Since visitors are not allowed to use audio recordings of the meetings, the quality of your meeting minutes cannot be overstated. Rather than transcribing the meeting’s dialogue, the minutes should summarize the discussion of your chosen topics, detail the resolution of complex issues, and describe the agreements and action items discussed. Within 15 days after the meeting, the Submitter must send the meeting minutes to FDA for their review. FDA will either accept the meeting minutes or provide edits for the Sponsor. The meeting minutes provide a formally documented account of the meeting discussion, which outlines regulatory requirements and FDA’s recommendation and expectations for future premarket submissions.
Use your time wisely. Following your submitted agenda, only discuss information included in the Pre-Submission. You may want to discuss the clinical study strategy, but if this was not included in the Pre-Sub, FDA will not be able to provide feedback. Submitters are advised to avoid discussing topics not included in the Pre-Sub and to limit the number of substantial topics/questions submitted to 3-4, but minor straightforward questions that don’t require supplementary discussion may be appropriate.
Some common topics and questions discussed during meetings:
Describe study designs and their rationale
Submitters may ask FDA if they agree with their chosen model, exclusion/inclusion criteria, or data acquisition/analysis methods
While asking for feedback on current or future studies is appropriate, the FDA remarks that requesting feedback is most effective prior to the initiation of testing
Note: Special considerations (e.g., nonsignificant risk device study, IDE exempt device, or studies conducted outside the US) may want to consider submitting their study protocols in the Pre-Sub prior to initiation, especially if it may raise special scientific or regulatory considerations
Although data review is not appropriate for Pre-Subs, data or conclusions that are difficult to interpret may warrant discussion with FDA to strengthen interpretation and resulting methods in future submissions.
Opportunity to detail approval strategies and receive feedback in areas that had not been considered.
Issues caught at this stage can better inform the next steps in product development or the submission process and potentially prevent the future loss of time and money.
How Can Sponsors Submit a Pre-Submission?
Medical device companies are certainly able to prepare and submit a Pre-Submission on their own. However, utilizing a medical device regulatory expert can help first-time applicants get acquainted with the program and regulatory submission processes and increase the likelihood of an effective Pre-Submission meeting. The team at Folio Consulting Group, LLC (FCG) has a wealth of experience preparing FDA Pre-Submissions and leading Pre-Submission meetings with the Agency. Specifically, FCG can help you:
Develop strategic questions to get all of your critical FDA feedback
Prepare the Pre-Submission package
Provide feedback on your regulatory strategy and test plan, including biocompatibility, shelf-life, sterilization, packaging validation, labeling, performance testing, usability testing, and clinical study strategy
Compile and submit the eCopy Submission following FDA eCopy Guidance
Help your team prepare for the Pre-Submission meeting by making slides and preparing an Agenda
Lead or participate in the Pre-Submission meeting
Record meeting minutes and submit these to FDA within 15 days
Schedule a free, 30-minute initial consultation with our experts at Folio Consulting Group, LLC to see how we can provide your team with regulatory assistance and help prepare your Pre-Submission.