510(k)

How much a 510k costs is the most common question I receive from customers, and there are three parts to the cost of a 510k.

There are three parts to the 510k cost of submission:

1. Testing
2. Submission Preparation
3. FDA User Fees

The highest cost is testing

The testing cost is the most significant cost, but I think the average is around $100K for our clients. For devices that only consist of a software (i.e., software as a medical device or SaMD), the testing costs are less, but the cost of documenting your software validation and cybersecurity will be more extensive than the cost of preparing your 510k and the FDA user fee. The more you can do in-house, the lower the testing costs will be. Biocompatibility testing for a non-invasive device might be only $13,000, but a long-term implant can cost as much as $100,000 for implantation studies. Sterilization validation testing depends upon the method of sterilization and whether you are doing a single-lot method or a full validation. Typical costs for EO sterilization validation are around $15,000, and then you should add several thousand more for the shelf-life testing.

For devices that are powered and/or have software, you will need to perform software validation in accordance with IEC 62304 ed 1.1 (2015). There are also five FDA guidance documents that apply:

1. General Principles of Software Validation; Final Guidance for Industry and FDA Staff (January 2002)
2. Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices (May 2005)
3. Guidance for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices (September 2019)
4. Guidance for Industry and Food and Drug Administration Staff Content of Premarket Submissions for Management of Cybersecurity in Medical Devices (October 2014)
5. Guidance for Industry, FDA Reviewers and Compliance on Postmarket Management of Cybersecurity in Medical Devices (December 2016)

You can do all of the software validation in-house, but some firms outsource the software validation. In the long term, you need to learn this, and it pays to hire an expert in IEC 62304 to help your team learn how to document software validation if you have not done this before. Typically, software validation documentation will be between 300 and 1,000 pages long.

Electrical safety and EMC testing are often the most expensive part of the testing process for our customers. EMC testing should always be done first to ensure you can pass the immunity and emissions testing. If you must modify the device to pass the EMC testing, you must repeat any electrical safety testing. The total cost of this testing is typically $50-60K.

Performance testing is the last part of the testing process. Performance testing should be performed on sterile and aged products if your product requires sterility and claims a shelf-life. Most of the testing is benchtop testing only to demonstrate performance. This includes simulated use testing (e.g., summative usability testing), cadaver testing, and computer modeling. Benchtop performance testing typically takes tens of thousands of dollars to complete, but you might be able to do the testing in-house. If animal testing is required, this typically costs around $100K. Finally, if a human clinical study is required (i.e., ~10% of 510k submissions), you should expect to spend between $250K and $2.5 million. Some simple clinical studies (e.g., IR thermometers) cost less than $100K, but these resemble benchtop performance testing in many ways.

The second highest cost is the cost of submission preparation

Medical Device Academy has two different options for preparation consulting fees. Your first option is hourly consulting fees. The second option is a flat fee. As of July 2023, we are charging $3,500 for pre-submission preparation and $17,500 for 510k submission preparation.

510k cost #3 is the cost of the FDA user fee

You have three options for your FDA user fees:

1. Third-party review
2. FDA review (standard user fee)
3. FDA review (small business user fee)

The first option is to avoid the FDA altogether and submit to a third-party reviewer. We only recommend one third-party reviewer (i.e., Regulatory Technology Services), because the other companies do not have sufficient experience to have predictable review times and positive outcomes. The typical RTS third-party review cost is 6% more than the FDA Standard fee.

The second option is to submit directly to the FDA. The standard user fee for FDA review of a 510k is $21,760 for FY 2024.

The third option is to apply for small business status. For companies that have annual revenues of less than $100 million USD, the FDA will grant you small business status. For companies with small business qualifications, the FDA user fee is reduced to $5,440.

Reduce 510k cost by applying for small business status

Any medical device company with revenues of less than $100 million annually can apply, but you must apply each year. There is no application fee, but you must complete FDA Form 3602 if you are a US firm. The form must be completed for each subsidiary too. FDA Form 3602A must be completed for foreign firms, and the national tax authority must verify the accuracy of your income statement on the form to submit it to the FDA. If your national tax authority refuses to sign the form, you can justify it, but I don’t know anyone who has done this yet. The qualification review by the FDA requires 60 days. Therefore, you should apply every year in August for the next fiscal year (October 1, 2023 – September 30, 2024, is FY 2024). The form will request that you include your Organization ID #. A Dun & Bradstreet Number (DUNS #) is also required if your firm is located outside the USA. Finally, you need to attach a copy of your tax return. Therefore, you must file your tax return–even if your firm had a loss or had no revenues. You can also use R&D tax credits in the USA or Canada if you are a start-up device company developing a new device.

About the Author

Rob Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certifications. From 2009 to 2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone at 802.258.1881 or by email. You can also follow him on Google+, LinkedIn, YouTube, or Twitter.

A poor RTA response will cause a two-week delay, but an additional information request only gets one chance to avoid the dreaded NSE letter.

An Additional Information Request (i.e. AI Request) is typically received just before the 60th day in a 90-day 510k review, while a Refusal to Accept (RTA) Hold is typically received on the 15th day. If your response to your first RTA Hold (i.e. RTA1) is inadequate, the reviewer will issue another RTA Hold letter (i.e. RTA2) and your 510(k) review clock will be reset to 0 days. You will have another 180-days to respond to RTA2, and issues identified in an RTA Hold are usually easy to address. Most RTA Hold issues also have one or more guidance documents that are available to help you to obtain an RTA Accept letter. You can always request a submission-in-review (SIR) meeting to clarify what information the reviewer needs to address the RTA deficiencies too. If you want to learn more about responding to an RTA Hold, please read last week’s blog. The rest of this article is specific to responding to requests for additional information.

What happens after 60 days during a 510k review?

On the 60th day of the 510k review clock, or a few days prior to the 60th day, the lead reviewer must determine if they need to issue an Additional Information (AI) Request. The alternative to an AI Request is for the lead reviewer to issue a letter indicating that you have entered the Interactive Review Phase. This only happens if the reviewer believes they can make a decision regarding substantial equivalence in the next 30 days. If the decision is to issue an Interactive Review Letter, then the lead reviewer believes that only minor issues remain and there is only the need for interactive email responses between the lead reviewer and the submitter. An interactive review is the ideal outcome of the substantive review process but it rarely happens.

If you receive an Additional Information Request, what are your options?

The AI letter will indicate that you have 10 days to request a clarification meeting with the reviewer. The wording of this section of the AI letter is provided below:

“FDA is offering a teleconference within 10 calendar days from the date on this letter to address any clarification questions you may have to pertain to the deficiencies. If you are interested in a teleconference, please provide (1) proposed dates and (2) a list of your clarification questions via email at least 48 hours before the teleconference to the lead reviewer assigned to your submission. We would like to emphasize that the purpose of the meeting is to address specific clarification questions. The teleconference is not intended for the review of new information, test methods, or data; these types of questions could be better addressed via a Submission Issue Q-Submission (Q-Sub). For additional information regarding Q-Subs, please refer to the Guidance for Industry and FDA Staff on Medical Devices: Requests for Feedback and Meetings for Medical Device Submissions at https://www.fda.gov/media/114034/download.”

If you wait too long to request the teleconference, then FDA will require you to submit a formal pre-sub request or “Submission in Review” (SIR) meeting request. If you request a SIR meeting within 60 days of receiving an AI Request, the FDA will schedule a SIR meeting with you within three weeks of receiving the request–assuming resources are available. If you wait longer than 60 days to request the SIR meeting, then the FDA will default to their normal target of 60-75 days for scheduling a pre-sub meeting. For example, if you submit your SIR meeting request on day 75, and the FDA takes 75 days to schedule the meeting, you will be granted your SIR meeting at 150 days and you will only have 30 days remaining to respond to the AI Request before your submission is automatically withdrawn.

Therefore, it is important to request a clarification meeting immediately after you receive the AI Request. While you are waiting for your clarification meeting, you should immediately begin preparing any draft testing protocols that you want the FDA to provide feedback on during a SIR meeting. Then after you have the clarification meeting, you should submit your SIR meeting request and include any draft testing protocols you have prepared. This may include a statistical sampling rationale, a proposed statistical analysis method, a summative usability testing protocol, or a draft protocol for some additional benchtop performance testing. The FDA can review examples of preliminary data, a protocol, or a proposed method of analysis. The FDA cannot, however, provide a determination of substantial equivalence.

The Most Common Mistakes in Responding to an Additional Information Request

Most companies make the mistake of asking the lead review if they provide specific additional information, “Will this be sufficient to obtain 510(k) clearance?” Unfortunately, the FDA is not able to provide that answer until the company has submitted the additional information and the FDA review team has had time to review it thoroughly. This is done only when the submitter delivers an FDA eCopy to the Document Control Center at CDRH, and the review team is able to review the information. This new information is assigned a supplement number (e.g. S001), and it will typically require three weeks to review the information. Then the lead reviewer may request minor modifications to the labeling, instructions for use, or the 510k summary. This request is an interactive request, and the submitter must respond within a very short period (e.g. 48 hours), and the wording of the request may be “Please provide the above information by no later than COB tomorrow.”

FYI: “COB” means “close of business.” Wow. The FDA loves acronyms.

Best Practices in Responding to an Additional Information Request

If you receive an AI request on a Friday afternoon, 58 days after your initial submission, you should immediately request a clarification teleconference with the FDA reviewer for the following week. The only exception is if you only have minor deficiencies that you feel are completely understood. During the days leading up to the clarification teleconference, your team should send a list of clarification questions to the lead reviewer and begin drafting a response memo with a planned response to each deficiency. After the clarification meeting, you will have approximately 6-7 weeks to submit a SIR meeting request. However, you should not wait that long. Your team should make every effort to submit your SIR meeting request within 2-3 weeks. If the FDA takes 3 weeks to schedule your meeting, then you will have used approximately 6 weeks of your 26 weeks to respond to the AI Request.

In your SIR meeting request, you should always try to provide examples or sample calculations to make sure the FDA review team understands what you are proposing to submit in your supplement. For example, the FDA reviewers do not have enough time to review your entire use-related risk analysis (URRA) in a SIR meeting request. However, you can provide an example of how you plan to document a couple of use-related risks. Then you can show how these risks would translate into critical tasks. Finally, you could provide a draft summative usability testing protocol for FDA feedback. The FDA review team doesn’t have enough time available to review much more. You will only have one hour for your SIR meeting.

How to Prepare Your Response

In section “V” of the FDA guidance on deficiency responses, the FDA recommends that you restate the issue identified by the reviewer in your response. Next, your response should include one of the following:

1. the information or data requested, or
2. an explanation of why the issue is not relevant, or
3. alternate information with an explanation of why the information you are providing addresses the issue.

Before you respond to an AI Request, you should look up any FDA guidance documents referenced in the AI Hold letter to make sure that you address each requirement in the applicable FDA guidance document(s).

The most important technique to learn when you are responding to regulators is to organize your response in a tabular format that is numbered in exactly the same order that the request was made. Typically there will also be sub-parts to certain issues. In that case, you should duplicate the numbers and/or letters of each sub-part and segregate each sub-part in a different row of the table. Personally, I like to alternate the color of the font I use in the table to make it even more obvious which information is a restatement of the reviewer’s comment and which information is the company’s response to the AI Request.

Why you don’t get a second chance to respond to an AI Request

Once you respond to an AI Request, and the DCC receives your FDA eCopy, the FDA review clock will then resume the countdown to 90 days. In our example above, you received the AIR Request on the 58th day. The FDA must review everything you submitted and make a final substantial equivalence decision before the 83rd day because they still need to submit their recommendations to senior management in their branch. If any changes to the labeling, instructions for use, or the 510k are required, you should receive those requests several days before (i.e. 76-83 days). You can respond to interactive requests via email, and then the final SE decision will be made. If you do not respond to all of the deficiencies in the AI Request, the FDA reviewer will not have enough time to request that you address the remaining gaps and finish their review. Therefore, an incomplete AI Response will certainly result in a non-substantial equivalence (NSE) letter.

If you need to respond to an additional information request from the FDA reviewer, we can review your planned response to identify potential gaps. If you need help please use our calendly app to schedule a call with a member of our team.

About the Author

Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.

When an FDA reviewer places your 510k on RTA Hold, there are secrets you can learn to improve your chances of a successful response.

Test your knowledge about the FDA RTA Hold process

Did you know that approximately 50% of 510(k) submissions are placed on RTA Hold? Did you know that you can be placed on RTA Hold multiple times for the same submission? Did you know that the 90-day review clock is reset to “0” when you submit your response? Do you know how to respond to the FDA when the reviewer is incorrect? Did you know that you can avoid the RTA screening process for any 510(k) submission if you use the correct template? Every year there are more than 1,000 submissions placed on RTA Hold, but did you know there is an FDA guidance specifically telling you how to respond to deficiencies? You can learn the secrets to responding to an FDA RTA Hold just by reading this article.

What is an FDA RTA Hold?

When the FDA receives a Traditional 510k submission FDA eCopy, the eCopy is uploaded to the FDA system within hours of the submission being received. If the eCopy does not meet the eCopy format requirements, then the submission will be placed upon eCopy Hold. The official correspondent will receive an automated email indicating that the submission is on eCopy Hold, and the submitter will be asked to correct the submission format to meet the eCopy submission requirements and provide a replacement eCopy. If the FDA user fee has not cleared, then the submission will be placed on User Fee Hold. It is possible to be placed on eCopy Hold and User Fee Hold at the same time.

If your eCopy is accepted, then a reviewer is assigned to screen your submission for compliance with the FDA Refusal to Accept (RTA) policy. The reviewer has 14 days to complete this review, and on the 15th day the reviewer must do one of three things: 1) issue a RTA Hold letter to the submitter, 2) issue an RTA Acceptance letter to the submitter, or 3) issue a letter that states the RTA screening was not completed on-time and the submission was automatically accepted. If your receive an RTA Hold letter, it will be via email from the reviewer and the RTA Checklist will be attached. In the checklist, there will some items highlighted in yellow and deficiencies will be noted in those sections. The reviewer may add additional comments to the checklist, but you are only required to respond to the highlighted sections. The process that the reviewer follows for RTA screening is defined in the FDA guidance for the Refusal to Accept process, and the guidance includes a checklist for traditional, abbreviated, and special 510k submissions. Some companies will fill in these checklists themselves and submit a copy of the checklist with the 510k submission. This is intended to help the reviewer identify where all of the requirements in the RTA checklist can be found. Third-party reviewers require that the company complete the RTA checklist and provide it to them with the eCopy.

How many times can you be placed on hold for the same submission?

Technically there is no limit to the number of times a submission can be placed on RTA Hold, and our firm has seen a few submissions placed on RTA Hold twice in a row. The first RTA Hold is referred to as RTA1, and the response to that RTA Hold is referred to as the first supplement (i.e. K123456/S001). If a second RTA Hold is issued, that hold is RTA2, and the response to that RTA Hold is referred to as the second supplement (i.e. K123456/S002). A response to an eCopy Hold is referred to as an amendment (i.e. K123456/A001).

What happens to the 90-day review clock when you are placed on RTA Hold?

When the FDA reviewer places your submission on RTA Hold, the 90-day review clock is automatically reset. Therefore, even if you respond to an RTA Hold on the same day you receive the RTA Hold, and your submission is received the next day, the “real” review timeline is now 106 days instead of 90. If your submission is placed on RTA Hold twice, then the “real” review timeline is now 122 days instead of 90. If the lead reviewer of your 510k requests additional information, this is referred to as an “AI Request.” We will address this in a future blog, but an AI Request does not reset the review timeline. The AI Request, however, will increase the review timeline. Although we rarely have an RTA Hold, we almost always have an AI Request. This is why our average submission is approximately 125 days (i.e. ~30 days are required to respond to the AI Request.

How should you respond if the FDA reviewer is incorrect?

The average 510(k) submission has grown over time from 300 pages to more than 1,200 pages, but the FDA review “clock” is still 90 days and the RTA screening is limited to 15 days. Therefore, it is not reasonable for you to expect the reviewer to understand and absorb every detail of your submission. If the reviewer can’t find the information they are looking for quickly, the reviewer may state that they could not find the information in the submission or that you did not provide it. If the information is found in the submission, you should provide a reference to the section of the submission, including the document and page number, in your RTA response. You may even choose to quote the information in your response memo if it is brief.

Other times the reviewer may not understand why certain information is not relevant to your submission. In this case, you should restate why the information requested is not relevant. You may want to review relevant FDA guidance documents that explain how to justify why information is not required.  For example, if you did not provide biocompatibility testing reports for some of the endpoints that are identified in ISO 10993-1:2018, then you should either provide a detailed biological risk assessment in accordance with the FDA guidance on the use of ISO 10993-1, or you should provide a biocompatibility certification statement.

If you are not sure why the FDA reviewer stated the information you provided is not acceptable, you might try calling or emailing the reviewer to ask for clarification. If you do this, be respectful of their time and be brief. You should identify who you are (you must be the official submission correspondent to speak with the reviewer), you should identify which submission you are contacting the reviewer about (they are working on many simultaneously), you should restate the issue identified by the reviewer (it may have been an issue of another member of the review team), and then you should indicate where the information can be found in the submission. If they believe this addresses the issue, then they will instruct you to provide that information in an RTA response. If the information does not address the issue, usually they will explain why. Your chances of receiving an email response are also better than speaking to the person on the phone–especially during the Covid-19 pandemic.

FDA eSTAR submissions are not subjected to the RTA screening process

When you use the FDA eSTAR submission instead of creating an eCopy, your submission should already meet all of the RTA screening requirements. The eSTAR includes automation to validate that the submission is administratively complete and therefore the reviewer does not need to do an RTA screening of an eSTAR submission. Therefore, most companies should realize a shorter overall 510k clearance timelines, because they will only have an AI Request and the review clock will not be reset.

Does the FDA offer any guidance on how to respond to deficiencies?

When the FDA writes deficiencies, the reviewer is supposed to follow the FDA guidance for deficiency content and format. However, the RTA checklist deficiencies typically are shorter and may not be as clear as a deficiency in additional information (AI) requests or non-substantial equivalence (NSE) letters. The first part of the deficiency is a reference to the information that was provided by the submitter (i.e. section, page number, or table). In an RTA checklist, each deficiency is provided in the comments section at the end of the section of the checklist. Therefore, if you have a deficiency related to your device description, the deficiency will be written at the end of the device description section of the RTA checklist. The comment will be highlighted in yellow, and there will be a checkbox next to the specific checklist item indicating that the requirement was not met. In the far-right column of the checklist, there will be a reference to the page of the submission where the deficiency can be found.

In the comment there reviewer should explain why the current information does not meet the requirement of the RTA checklist. The reviewer should also clarify the relevance of the deficiency with regard to the substantial equivalence determination. For the example of a deficiency related to your device description, usually, the issue is that your submission has inconsistencies between the various submissions or there is insufficient detail about your device. At the end of the comment, the reviewer should provide an explicit request for the information needed to address the RTA Hold.

In section “V” of the FDA guidance on deficiency responses, the FDA recommends that you restate the issue identified by the reviewer in your response. Next, your response should include one of the following:

1. the information or data requested, or
2. an explanation of why the issue is not relevant, or
3. alternate information with an explanation of why the information you are providing addresses the issue.

Before you respond to an RTA Hold, you should look up any FDA guidance documents referenced in the RTA Checklist to make sure that you address each requirement in the applicable FDA guidance document(s).

The most important technique to learn when you are responding to regulators is to organize your response in a tabular format that is numbered in exactly the same order that the request was made. Typically there will also be sub-parts to certain issues. In that case, you should duplicate the numbers and/or letters of each sub-part and segregate each sub-part in a different row of the table. Personally, I like to alternate the color of the font I use in the table to make it even more obvious which information is a restatement of the reviewer’s comment and which information is the company’s response to the RTA Hold.

Regardless of how well your response is organized, you must respond within 180 days. On the 181st day, your submission will be automatically withdrawn. The agency has granted extensions of an additional 180 days during the Covid-19 pandemic, but that will end and you should verify if you can obtain an extension from the reviewer rather than assume that this will happen. If the 180th day is on a weekend or US holiday, the Document Control Center (DCC) at the FDA will not receive your submission until the next business day. Therefore, you will need to ship your submission earlier to ensure the delivery is received on time. Since most companies are shipping their RTA response via FedEx or UPS to the FDA, you also will want to make sure you take into account customs clearance for international shipments and local holidays where you are. If you are shipping from the UK, for example, you can’t expect FedEx to ship on a British holiday. If you need help with printing and shipping your RTA response, Medical Device Academy offers an eCopy print and ship service for $99/eCopy (including the overnight FedEx fee).

If your 510k submission was placed on RTA Hold by the FDA, we can help you respond to the deficiencies identified by the FDA reviewer. We can also review your planned response to identify potential gaps. If you need help please use our calendly app to schedule a call with a member of our team.

About the Author

Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.

The US FDA does not require that 100% of your quality system be implemented before 510k clearance, but these 10 activities need to be done.

The form above allows you to register for a live webinar we are hosting on Friday, May 21, 2021 @ 1 pm EDT. The webinar will share the 510k project management lessons learned by our team since 2016. In addition to 510k project management, MedTech companies also need to implement their quality system in parallel with their regulatory submissions. Some people say that you need to implement your quality system before you submit your 510k. That is not an FDA requirement, but you do have quality system activities that need to be done before you will have all of the technical documentation you need to submit a 510k. This article describes 10 quality tasks you need to prevent unexpected delays.

Design & Risk Management Planning

Design & Risk Management Planning is your 1st priority because you want to identify all of the major activities that need to be completed in your design and risk management processes and which activities are critical path items. Otherwise, you will have unexpected delays. You can and should add details to the plan as you go, but items 2-9 listed below should be included in that initial plan–along with your design and risk management activities.

Risk Management Activities are Needed Before 510k Clearance

Risk Management is your 2nd priority because it’s an input to almost everything else listed below – this includes hazard identification, creating a use-related risk analysis (URRA), and identifying cybersecurity risks if you have software/firmware. Reference: ISO 14971:2019 Medical devices — Application of risk management to medical devices. Cybersecurity depending on the device should evaluate security as an overlapping but separate area from risk management. (Reference AAMI TIR57: 2016 Principles For Medical Device Security – Risk Management.)

Formative Usability Testing

Formative Usability Testing is your 3rd priority because this helps you evaluate your device design while it’s still evolving. Formative testing helps you identify opportunities for improvement, provides confirmation that your design is moving in the right direction, and identifies potential use errors while there is still time to implement effective risk controls such as alarms and other safety features. References:

• Applying Human Factors and Usability Engineering to Medical Devices Guidance for Industry and Food and Drug Administration Staff (2016)
• IEC 62366-1:2015 Medical devices — Part 1: Application of usability engineering to medical devices / AMD 1:2020

Software Validation is Needed Before 510k Clearance

Software Validation is your 4th priority because it must precede electrical safety testing for electromedical devices and most companies underestimate the time required to document software validation in accordance with IEC 62304:2006 / AMD 1:2015 and the FDA’s five guidance documents:

• General Principles of Software Validation:2002
• Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices:2005
• Off-The-Shelf Software Use in Medical Devices:2019
• Content of Premarket Submissions for Management of Cybersecurity in Medical Devices:2014
• Postmarket Management of Cybersecurity in Medical Devices:2016

Supplier Qualification is Needed Before 510k Clearance

Supplier qualification is your 5th priority because you do not want to order all of your prototype parts for the initial testing parts and then find out that the supplier is not capable of supporting you commercially. If you have to switch suppliers you might be forced to repeat biocompatibility testing and other design verification testing due to changes in the manufacturing process. Implementation of a supplier qualification process before 510k clearance is needed.

Label & IFU Requirements Specifications

Label requirements and instructions for use requirements specifications is your 6th priority because you cannot perform electrical safety testing or design validation (including summative usability testing) of your device without labeling and instructions. These requirements are the design inputs for information provided to the user and these must be controlled under design controls rather than document control.

Packaging Specifications

Packaging specifications is the 7th priority you should implement before 510k clearance because the packaging is needed to maintain sterility, to ensure product stability, and to protect the product from shipping. Companies are also frequently surprised by the long lead times associated with ordering custom packaging and you may not have the budget to validate sub-optimal “stock” packaging for your 510(k) submission and then repeat the validation for the optimized packaging later.

Quality System Implementation

Quality system implementation is the 8th priority for implementation before 510k clearance because you will need a fully functional quality system by the time your 510(k) is cleared. Quality system implementation typically takes 6+ months while the 510(k) review should take 4 months or less. Quality system implementation includes writing 25+ procedures, reviewing and approving those procedures, training your employees, and actually using those procedures to begin generating quality system records. For companies that are pursuing Canadian Licensing or CE Marking, the quality system must be fully implemented and certified before the regulatory submission is possible. (Quality System Requirements for the U.S. FDA are outlined within 21 CFR 820-Quality System Regulation)

Summative Usability Testing

Summative usability testing should happen after Design Freeze or you risk having to backtrack in your design process if this validation test reveals a need for device changes. The FDA’s 2016 Usability Guidance explicitly defines this validation testing as just a portion of overall design validation. (Reference Applying Human Factors and Usability Engineering to Medical Devices Guidance for Industry and Food and Drug Administration Staff (2016))

Apply for Small Business Status Before 510k Clearance

Application for small business status should be the 10th priority for implementation before 510k clearance because this can save your company $16,000+ but it requires that you submit your application at least 60 days before you need to pay the 510(k) user fee.

About the Author

Matthew Walker – QMS, Risk Management, Usability | Human Factors Engineering, Cybersecurity & DFIR

Matthew brings a unique background as a former Firefighter/EMT and Rope Rescue Tech with expereince in OSHA and NFPA regulations. For the better part of a decade, he has worked as a Technical/Medical Writer and Lead Auditor. He holds degrees in Fire Science and Computer Forensics and Digital Investigations, graduating Summa Cum Laude from Champlain College. Matthew is also an active member of several academic honor societies including Omicron Sigma Sigma’s Order of the Sword and Shield. His professional focus includes Human Factors Engineering, Risk Management, and Cybersecurity with a special interest in applying Digital Forensics and Incident Response (DFIR) practices to medical technology. He combines regulatory expertise with technical insige to strengthen both product safety and oranizational resiliance. He can be reached by email. You can also follow him on LinkedIn or YouTube.

This blog summarizes the changes in FDA policy, released on April 27, 2020, as a new eCopy guidance for device manufacturers.

The date of the guidance above was updated, but the changes to the guidance do not represent any changes in policy. It is an update of contact information and a note regarding eCopies for EUA requests. In August 2016, I had a frustrating week where I had three (3) different submissions placed on eCopy hold by the FDA, three (3) separate times, for a total of nine (9) eCopy hold in the same week. That resulted in an extra $175 of FedEx charges and wasted six (6) USB flash drives. The biggest problem was the submission delay experienced by each client that week, which wasn’t very comfortable. This terrible, no good, dreadful week ultimately resulted in our company creating a new productized service–preparing FDA eCopies for clients and competitor consultants. We also became international experts on the FDA eCopy guidance. If my experience was this painful, there must be other people experiencing the same problem, or many people would experience this problem as soon as they tried to submit their next filing with the FDA.

For about 18 months, we helped many companies prepare FDA eCopy submissions, but then there was a government shutdown, and the FDA unofficially changed its policy. A printed paper copy of pre-submissions, 510ks, and De Novo classification requests would no longer be required. You only needed to print a paper copy of your cover letter and include an electronic copy on a CD, DVD, or USB flash drive. Despite this policy change, many clients still requested the printed copy because the FDA legislation was not yet changed, and there was no updated guidance. We explained to each client that the policy had changed, and only two clients asked us to print the paper copy anyway.

In October of 2018, the unofficial policy became official, but there was still no updated FDA eCopy guidance for us to share with clients. This situation frequency resulted in questions from clients about how they should phrase the “eCopy Statement” in their submission cover letter. The eCopy guidance that was current in 2018 stated that you should include the following phrase in your cover letter: “This submission includes an eCopy and a paper copy. The eCopy is an exact duplicate of the paper copy.” However, the paper copy consisted only of the cover letter, and the rest of the submission was solely provided in electronic format.

The FDA released a new pilot version of the eSubmitter software to help companies prepare 510(k) submissions and to streamline the FDA review of submissions in 2018. However, even electronic submissions prepared with eSubmitter must be sent by courier or mail to the FDA Document Center. In 2019, the FDA mentioned that they would be releasing new guidance documents regarding electronic submissions. Still, we were also told that the FDA has no near-term plans to enable companies to submit pre-submissions, 510ks, or De Novo classification requests to the FDA via an electronic submissions gateway (ESG).

Finally, on December 16, 2019, the FDA released a new eCopy guidance. The eCopy guidance was updated again on April 27, 2020, but the changes are updated to include emails, updated webpages, and a note regarding EUA requests.

July 2022 Update for the FDA eCopy process

The FDA created a Customer Collaboration Portal (CCP) for medical device manufacturers. Originally, the portal’s purpose was to provide a place where submitters can track the status of their submissions and verify the deadlines for each stage of the submission review process. Last week, on July 19, the FDA emailed all active FDA CPP account holders that they can upload both FDA eCopy and FDA eSTAR files to the portal 100% electronically. Since our consulting team sends out submissions daily, everyone on the team was able to test the new process. If you have a CCP account, you no longer need to ship submissions via FedEx to the Document Control Center (DCC).

What DID NOT change in the new eCopy guidance?

The file name requirements are identical. You can still organize your submission in volume structure or document-only structure. You are still limited to PDF file sizes of 50 MB. The eCopy will still be problematic for the FDA to upload if your submission exceeds 1 GB. You still need to ship your eCopy to the FDA Document Center unless you submit it to CBER instead of CDRH. You can and should continue to use the eCopy validation software module provided by the FDA to ensure that your eCopy will properly upload. The guidance barely changed in length; it’s just a few pages shorter now.

What DID change in the new eCopy guidance?

Only two things changed in the new guidance. First, there is no mention of an eCopy statement anywhere. Second, you must submit a cover letter in paper format (replaced by Zip file to FDA CCP), but it does not need to be included in the electronic format (that’s only recommended).

The “new” eCopy process is not any easier than the process we have used since February 2018. However, we did update our cover letter template. If you would like a copy, please register for our FDA eCopy webinar.

Should you create your own eCopies, or should you outsource?

If my job was Director of Regulatory Affairs (or a similar position), I would outsource. Regulatory managers in companies are swamped with trying to remain compliant with new and revised medical device regulations and changes to applicable standards.

Does it take one hour to create an eCopy?

No, we can prepare, validate, and upload an FDA eCopy in less than 15 minutes. This is only possible because we do this almost every day. On the last business day before the end of the FDA fiscal year (September 30), we average four (4) submissions on that day alone. We know exactly what to do, we know how to fix all of the most common errors, we know our validation software module is up-to-date, and we never run out of USB flash drives (replaced by Zip files to FDA CCP).

How long could it take you to create an eCopy?

If you haven’t done an eCopy in that past year, it could easily take you all day to create an eCopy. You have to read the new eCopy guidance document. You must format your submission according to the rules and proofread 100% of the folder and file names. You need to find a new flash drive. You need to save the submission on your USB flash drive. You need to run the eCopy validation software module.

Or you could just outsource your eCopy problems.  

Today the FDA released a press release announcing plans to implement an alternate 510k pathway called the “Safety and Performance Based Pathway.”

What is the current 510k pathway for clearance of medical devices?

The current version of the 510k pathway is defined in a guidance document on a substantial equivalence that was released on July 28, 2014. The pathway involves six questions that an FDA reviewer must answer before it can be determined whether a new device is equivalent to an existing device that is legally marketed in the USA. These are the six questions:

1. Is the predicate device legally marketed?
2. Do the devices have the same intended use?
3. Do the devices have the same technological characteristics?
4. Do different technological characteristics raise different questions of safety and effectiveness?
5. Are the methods of evaluating new/different characteristics acceptable?
6. Does the data demonstrate substantial equivalence?
   

Five (5) ways the FDA strengthened the current 510k pathway

Today the FDA released an 8-page presentation summarizing five (5) ways that the FDA strengthened the current 510k pathway during the past several years. The five ways are:

1. Increased expectations for the content of a 510k submission
2. Implementation of the refusal to Accept (RTA) policy
3. Improved consistency and thoroughness of the 510k review process
4. Elimination of the 510k pathway for Class III devices
5. Eliminated the use of > 1,000 unsafe devices as legal predicates

You may have been complaining that 510k requirements seem to change constantly. Now you have proof that the changes to the 510k pathway are part of a strategic plan implemented over the past decade. Lawyers may argue that the resulting regulations go well beyond the intent of the original 510k legislation. This is completely true. The cumulative effect of implementing dozens of 510k guidance documents is that the official interpretation of the 510k section of the Food and Drug Act now has little resemblance to the original legal intent.

The original intent of the 510k legislation was to allow competitors to copy an existing device that is legally marketed in the USA. Cumulative changes to a device that existed in 1976, eventually result in a completely new device. The word “equivalent” has been perverted to such an extent that thousands of devices now exist that do not even remotely resemble devices from 1976. The FDA recognized this around 2007, and the US device regulations began to “strengthen.”  

What is the basis for the Alternate 510k Pathway?

The basis for the alternate 510k pathway is the submission of data that is safety and performance-based instead of comparison to an older predicate. In addition, the new pathway will enable you to make comparative claims by demonstrating that the new subject device meets or exceeds the safety and performance criteria. There is also a goal to use the pathway as a potential method of harmonizing the US medical device regulatory process with other global medical device regulations. The new process, combined with improved post-market surveillance, will complement the FDA’s work on NEST by allowing the FDA to rapidly require the implementation of risk controls to address identified safety issues.

What is the expected timeline for the implementation of the Alternate 510k Pathway?

The alternate 510k pathway has been in development for quite some time. Jeff Shuren first announced the plan to create the alternate 510k pathway at AdvaMed’s MedTech conference in San Jose, California, in September 2017. On Monday, December 11, 2017, the FDA announced that draft guidance would be released in Q1 of 2018. On April 12, 2018, the FDA finally released the draft guidance for public comment.

The FDA intends to release final guidance for the new alternate 510k pathway in early 2019. This pathway will initially be limited to “well-understood device types”–probably as a 510k pilot program. You can expect this new pathway to be released in a similar way to the Special 510k expansion pilot and the Quik 510k pilot. That final guidance will be released, and the pilot will begin immediately after the release of the guidance.

Is this new process likely to require significant changes to future 510k submissions?

The phrase “significant changes” is subjective, but if you look at the current 20 required sections of a 510(k) submission, there is only one section that would be required to change for the new alternate 510k pathway. Specifically, section 12 is currently used for a substantial equivalence comparison. This section would not be applicable under the alternate 510k pathway. Under the alternate 510k pathway, you can expect the FDA to require at least a summary of the safety and performance data to be submitted for approval of the subject device.

Another change you can expect is that all devices submitted under the alternate 510k pathway will be required to have a benefit-risk analysis in accordance with the corresponding FDA guidance. This new guidance was released on September 25, 2018, as a draft. However, a benefit-risk analysis is required for De Novo applications, CE Marking applications, and, logically, the FDA will also require this for 510k submissions that do not rely upon equivalence to the predicate device.

More Information on the Medical Device Safety Action Plan

The FDA created a webpage on its site, providing information about the Medical Device Safety Action Plan. The page includes several hyperlinks to documents with more information. Below are a few of the relevant links:

• Link for Downloading the Medical Device Safety Action Plan
• FDA Commissioner’s Statement on Modernizing 510(k) Program
• FDA Has Taken Steps to Strengthen the 510(k) Program – November 26, 2018

The FDA also indicated that a new guidance for De Novo applications would be released in a couple of weeks. Please subscribe to our blog, and you will receive notification of a blog in response to that guidance when it is released.

There are 38 product classification codes that the FDA selected for the Quik 510k Pilot program to evaluate version 3 of the eSubmitter software.

What are the three (3) advantages of the new Quik 510k pilot program?

There are three (3) advantages of using the eSubmitter software as part of the Quik 510k pilot.  The first advantage of using the eSubmitter software is that the refusal to accept (RTA) process will be eliminated. This change is enormous because nearly 50% of submissions are rejected during the RTA screening process. The hope is that the eSubmitter software will prevent companies from submitting submissions that are missing required content, and therefore the RTA process will not be needed. However, we have seen many submissions placed on hold for technicalities rather than sub-standard submissions. Consequently, it will be fascinating to see the FDA reported outcomes from the Quik 510k pilot.

The second advantage of using the eSubmitter software is that the reviews will be interactive. This means that reviewers are not expected to have any additional information (AI) requests. This also means that submitters will need to respond to questions from reviewers quickly. For example, I have received a call on Friday afternoon after 5:00 pm EDT asking if I could revise to document and email that document to the reviewer by Monday morning. This is an extreme example, but 48-72 hours is typical for a required turn-around during interactive reviews.

The third advantage of using the eSubmitter software is that the FDA is targeting completion of their 510k review within 60 days. This 30-day reduction may seem huge, but the FDA already cut 15 days off its review timeline by eliminating the RTA screening. Second, the FDA picked 38 product classification codes that should not have difficulty reviewing in 60 days. Not all product classifications have the same amount of testing data required, and I do not expect the FDA to be able to review all product classification codes in 60 days–even with eSubmitter.

Although the Quik 510k pilot mentioned that submissions would be zipped, eSubmitter is also designed for electronic submissions through an electronic submissions gateway (ESG). An ESG has the added advantage that you will not need to ship your submission via FedEx. This advantage will gain you only a maximum of 24 hours, but I wish I had those 24 hours last week. Every year, in the last week of September, all the small businesses with small business qualifications try to submit their 510k before the end of the fiscal year (i.e., September 30). This year I had four clients that were in this position. One was unable to get the data they needed to complete their submission before September 30. The other three were making last-minute changes up until the afternoon of Thursday, September 27. One of those submissions was extremely challenging because the submission included video files that exceeded 1GB in total. Therefore, I called CDRH’s eCopy Program Coordinators at 240-402-3717. They were accommodating. They said that it would be best to provide two identical eCopies or to save the MISC FILES and STATISTICAL DATA folders on a separate flash drive. The reason for this is that very large submissions can take days to upload into the CDRH database. Therefore, the picture below shows you what my final solution was for the three submissions this week. The De Novo submission had to be split.

What our firm has done to take advantage of the Quik 510k pilot

If you have a product with any of the 38 product classification codes listed above, and you need to submit a 510k in the next six months, you are very fortunate. The FDA will prioritize your submission, and you are likely to be able to get your device cleared in 60 days or less. Our firm is very anxious to take part in this pilot because the FDA intends to require the eSubmitter software for all submissions in the future, and we expect other product classification codes to be added to the pilot over time. We process dozens of 510k submissions each year, and mastering the nuances of the software is critical to our continued success. I already downloaded the software and installed it onto my computer. I also created a complete submission as a test. eSubmitter saved several hours in the preparation of a 510(k) from the typical 40 hours the process takes. Therefore, I expect the implementation of new eSubmitter software to a triple win for the FDA, clients, and our firm. I plan to request that the FDA add De Novo submissions next to this pilot. The reason is that De Novo submissions typically have more content, and the content is more variable. I think this would be an extremely challenging test for eSubmitter, and the relatively small volume of De Novo submissions would limit the impact upon FDA resources.

Changes to eCopy Requirements in 2018

In 2017, the FDA indicated that eSubmitter software was going to be revised, and it would be approximately two years before companies would be able to submit a 510k electronically to the FDA. Until then, companies must ship an electronic eCopy and a paper copy to the FDA Document Control Center (DCC). The eCopy guidance states, “An eCopy is accompanied by a paper copy of the signed cover letter and the complete paper submission.” However, the FDA’s eCopy guidance has not been updated since December 3, 2015. There are some unofficial changes to the policy, and the FDA no longer requires the complete paper submission. Instead, you can submit an eCopy accompanied by a paper copy of the signed cover letter.

Before February 2018, we would print 1,000+ pages for each 510k submission, pack two 3” three-ring binders in 12”x12”x6” ULine boxes and ship the box to the FDA overnight via FedEx. We typically would charge $400 for this eCopy service. After the unofficial policy change, all of our 510k submissions consist of a paper copy of the cover letter and an eCopy on a USB flash drive. We only charge $150 for the FDA eCopy service, and 100% of our eCopy submissions have been uploaded without problems this year.

What is the difference between creating an eCopy and submitting it with eSubmitter (cited from FDA website)?

There are four differences between eSubmitter and eCopies:

1. An eSubmission package contains PDF attachments and XML file types. The XML files are intended for CDRH IT systems to process the application. Reviewers will not see these XML files. 
2. The parts of the eCopy guidance that describe the structure of a 510(k) submission will not apply to the Quik Review Program Pilot.
3. An eSubmission is organized according to the layout of the template, which places administrative documents (e.g., Form 3674, the 510(k) Summary, the Truthful and Accurate statement) at the end of the submission because their applicability is determined based on the answers to questions in the body of the template (e.g., Form 3674 is only required if the applicant indicates clinical data are included).
4. Electronic signatures are used in the submission (e.g., on the Truthful and Accurate statement), rather than physical signatures.

eSubmitter Template Options

For device 510k submissions, the FDA’s eSubmitter gives you three options:

1. Template Version 1.3, for In Vitro Diagnostic 510k submissions to CDRH only, allows you to create a 510k submission and the eSubmitter software will package your submission in a specially formatted zip folder that you can save to a compact disc (CD), digital video disc (DVD) or flash drive. Then you must print a paper copy of your signed cover letter and ship the eCopy created by eSubmitter with your paper copy of the cover letter to the FDA DCC.
2. Template Version 1.2.1, for Non-In Vitro Diagnostic 510k submissions that are among the 1,000+ other product classifications not included in the Quik 510k pilot (CDRH: Medical Device eCopies), you can create a 510k submission and the eSubmitter software will package your submission in a folder for you. You can then copy the contents of that folder to a compact disc (CD), digital video disc (DVD), or flash drive. Then you must print a paper copy of your signed cover letter and ship the eCopy created by eSubmitter with your paper copy of the cover letter to the FDA DCC.
3. Template Version 3.2, for Non-In Vitro Diagnostic 510k submissions that are among the 38 product classification codes that are listed above for the Quik 510k pilot program. This allows you to create a 510k submission, and the eSubmitter software will package your submission in a specially formatted zip folder that you can save to a compact disc (CD), digital video disc (DVD), or flash drive. Then you must print a paper copy of your signed cover letter and ship the eCopy created by eSubmitter with your paper copy of the cover letter to the FDA DCC. This template is unique to the Quik 510k pilot program. There is a red bar that appears at the top of the screen:

“This template should only be used to construct a submission if you are submitting it as part of the Quick Review Pilot. All others may use the content of this template as a reference to aid in constructing an eCopy. If you are not part of the Quick Review Pilot, do not construct a submission with this template, it will be rejected.”

When you create your eCopy, then you will need to create a volume-based or non-volume based submission in accordance with the eCopy guidance. The volume folders and/or files are saved to a compact disc (CD), digital video disc (DVD), or flash drive. Then you must print a paper copy of your signed cover letter and ship the eCopy you created with your paper copy of the cover letter to the FDA DCC.

Warning: If you are using Windows 10, and you save your eCopy or eSubmitter zip folder on a flash drive, Windows 10 will automatically create a hidden system folder titled “System Information Volume.”  This folder is created as a security feature to enable you to recover accidentally deleted content. However, this folder results in an error when the FDA attempts to upload your submission automatically. Therefore, you must remove this hidden system folder. Instructions for this can be found on our website page about eCopy hidden system files.

This article is a copy of my responses to someone that submitted biocompatibility testing questions in preparation for a 510k pre-submission webinar.

Can you please answer the following questions related to biocompatibility for a 510k pre-submission meeting request?

This was the request by a person that registered for a 510k pre-submission webinar that was recorded in February 2018. The person asked some great questions that are very similar to other clients I work with. They also requested the biocompatibility testing questions in a way that did not divulge any confidential information–other than to indicate they live in Germany. Therefore, I am sharing my email response with you. Please register for this webinar and submit your questions. Questions are entered in an open text box, and you have room to ask multiple questions.

Biocompatibility testing question #1: Does the FDA now already ask for the AET (Analytical evaluation threshold) for chemical analyses?

Biocompatibility testing question #2: How can I avoid time-consuming genotoxicity studies for FDA?

Question #3: And how can I face FDA with a cytotoxic wound dressing but which passed irritation, sensitization, genotox, and pyrogenicity tests?

Biocompatibility testing question #4: Which genotoxicity tests are state of the art for the FDA?