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510k Submission, Section 14-Sterilization Validation and Shelf-life

Posted by on March 24, 2015

This article explains the process for preparing the sterilization validation and shelf-life section of a 510k submission.

sterilization validation 510k Submission, Section 14 Sterilization Validation and Shelf lifeSterilization validation and shelf-life, Section 14, is typically one of the last sections of a 510k submission to be completed. However, most of the work in preparing this section of your 510k submission should be completed more than a month before actually completing the associated testing. The reason why you can write this section, before receiving the results, is that your results are 99% predictable. If you are unlucky enough to be part of the 1% that have surprising results during sterilization validation, then you will need to make changes and repeat your testing.

Design Planning Aspects Related to Sterilization Validation

During your design and development process, sterilization validation testing is part of design verification testing—not design validation. This testing is verification, rather than validation because you are testing in accordance with recognized standards (i.e., design inputs) to ensure that the sterilization process parameters are adequate to consistently meet the sterility specification (i.e., design output). In your design plan, it is critical to understand which of the following three categories your sterilization process falls under:

  1. Traditional Sterilization (e.g., ethylene oxide)
  2. Non-traditional Sterilization (e.g., Hydrogen Peroxide)
  3. Novel, Non-traditional Sterilization (e.g., Chlorine Dioxide)

You must identify which category your sterilization process falls into because the review process used by the FDA for each category of the sterilization process is different. Traditional sterilization processes have recognized standards that a reviewer can easily compare your validation methods with.

Non-traditional sterilization methods are becoming more popular for products that are sensitive to degradation caused by high temperature, or exposure to radiation or ethylene oxide. However, the FDA has identified non-traditional sterilization processes as being a priority for inspection. Therefore, after your product receives 510k clearance, you can expect an FDA inspection sooner than products that use traditional sterilization methods (i.e., 6-12 months instead of 12-24 months). 

The novel, Non-Traditional Sterilization

The novel, non-traditional sterilization methods require a different 510k clearance process, because the FDA requires an internal consultation from the Infection Control Devices Branch (INCB) before issuing 510k clearance. A consultation is needed for evaluation of the sterilization process because reviewers lack sufficient expertise in the field of microbiology and Sterilization to evaluate novel sterilization processes. The INCB can also provide a consult for non-traditional sterilization processes, but this is not typically needed if the process is following established ISO Standards for sterilization validation. 

For the novel, non-traditional sterilization processes, and INCB consult is required, and it is recommended to consult with the FDA early regarding the use of this type of sterilization process. Part of the reason for this early consultation is that a pre-clearance priority inspection is required before issuing the 510k. The FDA published draft guidance on this topic in 2008 that can be found on the following webpage – Click Here.

The image below shows where the INCB is located within the hierarchy of the FDA’s organization.

incb 510k Submission, Section 14 Sterilization Validation and Shelf life

Creating Summary Technical Documentation (STED)

The sterilization validation and shelf-life section of a 510k submission may be copied from the summary technical documentation (STED) that you prepare for CE Marking applications or a Canadian Medical Device License Application. Instead of including all of the protocols and testing reports from your validations, the regulators only require a summary of the validation activities and results. If the STED is thorough and well-organized, the reviewer should not request validation reports. However, if the STED is incomplete, then the reviewer is likely to request a copy of the validation reports.

Any STED should include the following elements:

  1. Identification of the validation dates
  2. Identification of the organization(s) that performed the validation
  3. Reference to the ISO standard or other recognized standard that was used
  4. Identification of any deviations from the referenced standard
  5. Number of lots and samples per lot tested
  6. Description of the testing performed—including testing parameters
  7. Identification of the document control numbers and revisions for protocols and reports
  8. Acceptance criteria for the validation
  9. Summary of the results

For your STED specific to sterilization validation and shelf-life, you will also need to ensure you include a description of the packaging used to maintain the device’s sterility (primary packaging) and a description of the packaging used to protect the primary packaging (i.e., secondary packaging).

For a 510k submission, you will only need to make a few modifications to the STED that you use for European CE Marking and Canadian licensing. First, you need to ensure you are referencing standards recognized by the FDA. If you followed a different method, the differences need to be documented in Section 9 of your submission on FDA Form 3654 for each Standard.

Second, you will need to include a reference to Ethylene Oxide (EO) residual testing summarized in Section 15 for biocompatibility (not applicable to non-EO methods of Sterilization). EO residual testing must be performed in accordance with ISO 10993-7. You should also include an outline of the validation methods that were used in your comparison of substantial equivalence in Section 12 of your submission. Finally, you should reference the methods used briefly in your executive summary (i.e., Section 10) and the 510k summary (i.e., Section 5)—assuming that you did not use a 510k statement.

If you are writing your first STED for sterilization validation and shelf-life, I recommend reviewing the RTA checklist in advance.

You may want to organize your STED with headlines that address each of the questions outlined in the RTA checklist.

You should also be aware that although the FDA references the 2002 guidance document K90-1 for the format and content of the sterilization validation section, there is a 2008 draft guidance the represents the FDA’s current thinking on the topic of sterilization validation. That draft guidance document is also identified as a priority for the FDA to release as a final guidance in FY 2015 (i.e., before October 1, 2015).

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th, 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops

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Performance Testing for a 510k Submission-Case Study-Part 2

Posted by on March 10, 2015

Performance Testing for a 510k Submission-Case Study-Part 2 explains the performance testing for a 510k submission to obtain clearance from the US FDA for marketing a new medical device. Performance testing is an essential part of new product development and is usually the last section that you can complete before your submission.  510k part 2 Performance Testing for a 510k Submission Case Study Part 2 In my previous 510(k) case study article (http://www.MedicalDeviceAcademy.com/510k-submission-fda-case-study), I showed you how to research the FDA classification database to determine if there is a special controls guidance document to follow in the preparation of your 510k submission. The example I used was for topical adhesives (i.e., MPN). Topical adhesives do not have any Recognized Consensus Standards listed. Instead, all the performance testing requirements are specified in the special controls guidance document.

In this case study article, I selected a different product code that has Recognized Consensus Standards, but it does not have a special controls guidance document. After identifying the device classification and product code, if there is no Special Controls Guidance, you need to plan your performance testing based upon other sources of information. If there is no Special Controls Guidance document, I use three methods for determining what performance testing is needed:

  1. Look for any device-specific standards
  2. Review other 510k summaries
  3. Order previous 510k submissions via FOIA requests

For this case study, the product code selected was a bone fixation screw (i.e., HWC). The number of predicate 510k submissions to choose from for this product code is extensive. There are 29 from Arthrex alone. Some of these 510k submissions include a 510k statement, while others include a 510k summary. A statement is not directly helpful in identifying any of the performance testing that was used for the clearance of the potential predicate device. However, 21 CFR 807.93 requires that the company that submitted the 510k shall provide a redacted copy of the 510k submission within 30 days of the request. If this is requested early in your 510k project, you should have a copy of the submission in time to plan your performance testing for verification and validation of the subject device. You can also order predicate 510k submissions through the Freedom of Information Act (FOIA) request process:

(http://www.fda.gov/regulatoryinformation/foi/howtomakeafoiarequest/default.htm).

In the case of a 510k summary, the summary indicates what performance testing was performed to demonstrate substantial equivalence. In the case of K103705, the section titled “Substantial Equivalence Summary” states that mechanical testing data for torque and pull-out testing was submitted for the subject device and the predicate device. Other 510k summaries may provide additional data or a more descriptive list of testing that was performed. In the case of this 510k example, there is a second product code listed: HRS, bone fixation plate. The HWC bone fixation screw product code indicates that there are 5 Recognized Consensus Standards:

Only three of the above standards are included in the list of eight Recognized Consensus Standards related to the HWS product code. One of those eight standards should probably be covered under the HWC product code, as well:

Now you have a total of six different device-specific standards that can be used for planning the performance testing of your bone screw. This is significantly more helpful than a 510k summary that says torque and pull-out testing was performed. After you have ordered and reviewed each of the standards, you then create a list of performance tests that apply to your screw and create an overall verification and validation plan.

It is essential to perform this review each time, because there may be new or revised testing methods established as the Recognized Consensus Standards are updated. If you outsource testing, then you will need to obtain a quotation from a testing lab for each of the applicable tests.

Once you have created a comprehensive testing list, and you have quotations for all the testing required, you need to schedule the testing and ship samples to the testing lab. Once testing has begun, this is the best time to start the preparation of your 510k submission. Performance testing often takes several months to complete. If you start preparing the 510k before you have ordered the testing, then you are starting too early, and you may have to change your performance testing summary multiple times.

If you start your 510k preparation after you order your testing, then you can create the entire performance testing summary. The only information that you will be missing is the final report number for each test being performed. For the most part, you do not need the specific results of the testing, because the tests are designed to show that the subject device is “equivalent” or “not worse” in performance. Quantitative comparisons between your subject device and the predicate device are not allowed by the FDA for a 510k submission. Your subject device must be “equivalent” or “not worse than” the predicate device concerning safety and efficacy.

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th, 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops

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510k Submission to the FDA (Case Study – Part 1)

Posted by on March 2, 2015

This article is the first part of a two-part case study providing an overview of the premarket notification process (i.e., 510k submission) to obtain clearance from the US FDA for marketing a new medical device. This first part of the series focuses on the initial steps of a 510k submission project: 1) identifying product classification, 2) identifying any applicable international standards and special controls guidance documents, and 3) selecting a primary predicate device.

case study 510K 510k Submission to the FDA (Case Study Part 1)

For this case study, I chose the maker of Krazy Glue® as a hypothetical new client. The company wants to start selling cyanoacrylate as a topical adhesive in the U.S. market. As with the Canadian and European markets, the US FDA considers cyanoacrylate a medical device when it is used as a topical adhesive. The first step toward obtaining FDA clearance for marketing the new product is to determine the device’s classification.

Device Classification

My client was considering asking the FDA to identify the classification of topical adhesives using the 513(g) submission process. Still, I provided the following reasons why the client should not use the 513(g) process:

  1. the 513(g) process takes 60 days to get a response from the FDA, while a qualified consultant can make the same determination in less than a day
  2. hiring a consultant typically costs less than the 513(g) fee (i.e., $3,387 for large companies and $1,694 for small businesses)
  3. the FDA’s classification determination is non-binding, and the accuracy of the FDA’s response is highly dependent upon the quality of the information provided by the company

In this case, I was able to answer the client’s question about device classification over the phone without any charge. The client indicated that they wanted to launch a product similar to Surgiseal. I was able to use the US FDA Registration and Listing Database to identify the product classification by merely typing “Surgiseal” in the field for “Proprietary Name.” Adhezion Biomedical LLC is registered as the manufacturer of Surgiseal. The three-letter product code “MPN,” and the device is a Class II device requiring premarket notification via a 510k submission.

This product classification also gives my client additional options that are not available to all companies that are trying to achieve 510(k) clearance for the first time. Most new products can only achieve initial 510(k) clearance from the US FDA by submitting a “traditional” 510(k). This process is supposed to take 90 days—assuming there are no significant questions about the submission, and the reviewer has a manageable workload to review. The average time for determination of 510k clearance is currently between 120 and 180 calendar days.

Applicable International Standards & Special Controls Guidance

For some products, there are recognized consensus standards (i.e., ISO Standards) that define the performance requirements for a medical device or a Special Controls document published by the FDA that identifies which performance Standards the FDA requires for specific product classification. In the case of topical adhesives, the FDA has issued a Special Controls document. When there is a Special Controls guidance document available (http://bit.ly/FDA-topical-adhesive), the company may submit an Abbreviated 510k instead of a Traditional 510k submission.

An Abbreviated 510k submission contains summaries of all the testing results required in the Special Controls document or an ISO Standard recognized by the US FDA. Since all the testing of performance needed to be presented in an Abbreviated 510k submission is in accordance with a previously accepted standard, the FDA reviewer only has to verify that the performance testing identified in the Special Controls document or the ISO Standard has been completed and acceptance criteria have been met. Therefore, the reviewer needs less time, and the FDA’s performance target for making a clearance decision is 60 days—instead of 90 days.

In addition to Special Controls documents, the FDA also has guidance documents related to 510k submissions, such as: “Format for Traditional and Abbreviated 510(k)s.” By following this document verbatim, my client can avoid a lot of time-consuming questions from a reviewer that is having trouble finding the information they are looking for. If a section of the suggested format is not applicable, I still include this section. However, I indicate the reason why this section is not applicable in a brief paragraph (i.e., a one-page section).

As I read through the Special Controls Guidance document, I realized that a specific format for an Abbreviated 510k is described for topical adhesives. Therefore, I need to modify my normal template to match the FDA format for a topical adhesive Abbreviated 510k submission. As I read further, I realized that there would be some additional testing required that my client may not have anticipated.

In the Special Controls document, there are several risks and recommended mitigation measures identified:

fig.1 510k 510k Submission to the FDA (Case Study Part 1)

The risks of adverse tissue reaction, chemical burns, and infection have all been addressed by biocompatibility testing and sterility testing. My client also performed animal testing to identify any problems in a simulated use environment. However, the client did not perform any testing to address unintentional bonding specifically, wound dehiscence, applicator malfunction or delayed polymerization. The client needs verification protocols and test reports to address these specific risks.

Selection of a Primary Predicate

Another unique requirement from the US FDA for a 510k submission is the concept of a predicate device. A predicate device is a similar product that currently has a valid 510k. In July 2014, the US FDA released a guidance document that clarifies that companies submitting a 510k should identify only one primary predicate–rather than identifying multiple predicates. Ideally, a recent 510k submission should be selected because “old” technology may no longer be considered acceptable from a safety standpoint. In the case of topical adhesives, the applicator is one of the primary differences between legacy products and more recent 510k submissions. The most recent version of Surgiseal™ is an example of a new applicator for a monomeric, 2-octyl cyanoacrylate.

My client has a similar applicator design, and therefore Surgiseal™ is selected as the primary predicate device for this 510k submission. For all the testing protocols that need to be created for this 510k submission, comparative testing is performed with a sample of Surgiseal™ and a sample of products made by my client. In each of these protocols, the acceptance criteria are performance “not worse than Surgiseal™.” 

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” ships on Monday, February 6th, 2017. There is also an on-line 510k course series consisting of 24 webinars. Please visit my webinar page to purchase individual webinars. We also have live 510k workshops.

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Our 510k Project Management Tool – An Inside Look at Our Process

Posted by on February 16, 2015

This article explains our 510k project management tool, the 510k Table of Contents, and we provide a form to request a free template.

Table of Contents Screen Capture Our 510k Project Management Tool An Inside Look at Our Process

Despite all the perceived changes to the FDA’s pre-market notification process (i.e., 510k process), the format and content requirements have not changed much. The most significant change to the 510k process was the introduction of the Refusal to Accept Policy (now updated for 2019) in 2012. The RTA process did not, however, change requirements for format and content. The RTA process simply provides a checklist for reviewers to screen submissions to ensure the submission is complete and follows the required format. Actual content requirements can be found in a 2005 guidance document titled, “Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 510(k)s”. To ensure that you don’t deviate from this required format, use a standardized template for the Table of Contents.

Overview of our 510k project management tool

There are 20 sections to a 510k submission. For each section, Medical Device Academy’s consulting team created a template for the documents to be included in that section. Each section is assigned a volume number (i.e., 1-20), and typically there is an overview document for the section that is identified by Vol x Doc 1. We also use a consistent header and footer for every document to identify the subject device of the submission, the name of the section, and the volume/document numbers. In addition to the templates our consulting team created, several FDA forms must be used for specific sections. These forms are a mixture of MS Word® documents and PDF documents that must be edited in Adobe Acrobat®.

Table of Contents Used as our 510k Project Management Tool

When one of our consultants is starting a new 510k project, we use a spreadsheet version of the Table of Contents. This allows us to perform a gap analysis of the existing documentation available from the client. If the client owns the 510k for the predicate device, then the client may only need to update documents to reflect changes. If the client has a Technical File, then most of the information is available. Still, the consultant must revise the format and organization of the content to fit our 510k document templates. In one of the columns of the spreadsheet, the consultant performing the gap analysis makes comments about what is available and what needs to be done to complete the 510k submission.

Status of Documents

To communicate the status of documents in the gap analysis, and throughout the 510k project, the consultant will color code the sections of the table of contents:

  • green = ready for submission
  • blue = ready for the client’s review and approval
  • yellow = document requires revision and/or reformatting of content
  • red = the information does not appear to be available

Our consulting team also uses this same color coding approach when we create a Technical File or a Design Dossier for CE Marking. We will include cross-references to document and report numbers if controlled documents are available. We also add two columns to track our estimated and actual consulting time for the project. Estimated hours required to complete each section are provided, and then as the project progresses, we update the spreadsheet to include the actual time spent on each section.

Using Dropbox

We share the planning spreadsheet and the documents created for each section of the 510k submission with our clients using http://www.dropbox.com/. In each client’s Dropbox folder, we have sub-folders for the 20 sections of the 510k Table of Contents. As we finalize each document, the documents are reviewed and approved by the client. After final approval of the documents, each document is saved as a PDF–as required for eCopy submissions (updated in 2020). Periodic updates are provided to the client via conference calls. Still, the client can view progress on the overall 510k submission project in almost real-time by reviewing the 510k Table of Contents in spreadsheet form.

Team coordination using our 510k project management tool

We also use our 510k Table of Contents to help identify who is responsible for each section of a 510k submission. Not every consultant is an expert in electrical safety (section 17), biocompatibility (section 15), and pre-clinical animal studies (section 19). Most of Medical Device Academy’s consultants are specialists in a narrow discipline. Therefore, it is common for us to assign different sections to different consultants. By using the same templates and process for each submission, a team can work efficiently from 3 or 4 countries simultaneously on the same 510k submission.

Prioritizing Section Completion

Each section of the 510k submission must be completed, but the order of completing the sections is important. For example, we find that the first section to complete is in section 4–the Indications for Use. This section is essential because the Indications for Use should match the predicate device we are claiming substantial equivalence to in section 12.

Another section we like to work on very early in the project is section 13 for Proposed Labeling. The labeling includes the Instructions for Use (IFU), and the IFU must consist of a statement of the Indications for Use. The sections we prioritize last are the sections that summarize verification and validation testing that has been done. These sections are done last because we find we are almost always waiting for a test report at the end of the project. We also find that testing sometimes needs to be repeated.

Please fill in the form at the bottom of this page if you would like to receive Medical Device Academy’s template for the 510k Table of Contents. We updated our Table of Contents in 2021 again and you can receive a copy via email if you complete the AWeber form below and confirm your desire to receive email updates.

Additional 510k Training

The new 510k book, “How to Prepare Your 510k in 100 Days,” was completed in 2017 but the book is only available as part of our on-line 510k course series consisting of 24+ webinars. Please visit the webinar page to purchase individual webinars.

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The Three Biggest Changes in the Latest 510k Guidance

Posted by on September 5, 2014
510k pmn The Three Biggest Changes in the Latest 510k GuidanceThis blog describes the three most prominent changes in the latest 510k guidance document released on July 28, 2014.

This recently issued guidance (http://bit.ly/Substantial-Equiv-Guidance) for evaluating Substantial Equivalence (SE) is well written and informative, with well-chosen and written examples. For newbies to 510ks, this is the place to start. The guidance includes background information about the 510k process and links to other documents. If you are an experienced professional, this is a must-read insight into the FDA’s current approach. Use it to guide your strategy for your next submission, and make it as easy as possible for the reviewer to reach a decision of SE for your device.


Change #1: 510k Flowchart

The 1986 flowchart guiding the decision of SE was updated and re-formatted to improve clarity. A substantial part of the guidance explains the thinking process that guides a reviewer at each decision step. If you are in the middle of preparing a submission, as I am, then the guidance provides an opportunity to review your work against current FDA thinking and training and adjust your submission to align with the FDA.


Change #2: Predicate Selection

Much has already been written about how this document may alter your selection of a predicate device. The FDA clarifies that split predicates (one for intended use equivalence, another for technological equivalence) have been ruled out. The FDA also recently released another guidance document to assist with performing a benefit/risk analysis (http://bit.ly/SE-Benefit-RIsk) when you are developing a device with a different technology than the predicate. The checklist below is intended to help you review your submission when you have already chosen an appropriate predicate.

  1. If you are using multiple predicates, have you stated which one is your primary predicate, the one that is most similar to your device? The FDA must find your device substantially equivalent to one other device.
  2. Are you using secondary predicates only when you are combining features, have more than one intended use, or have additional indications for use?
  3. Is the intended use the same as that for the predicates? Carefully compare your Intended use and the Indications for use with those of the predicates. If they are worded differently, have you explained how they are nevertheless the same?
  4. Have you provided a rationale for your choice of predicates in a way that aligns with the guidance?
  5. Is your SE table organized such that the secondary predicates only support the additional indications for use?
  6. Has your predicate been involved in a design-related recall?
  7. Double-check the Indications for Use statement in your labeling. Regulations state that the determination of the same intended use must be made against the labeling, not against what you say in the submission. Of course, what is in the submission should match the labeling.
  8. Have you included a copy of the labeling for the predicate device, e.g., the user manual?
  9. Does your Description section have sufficient information about the technical characteristics? The FDA is quite specific about what they want to see. Check your Description against the lists on page 19, and at (http://bit.ly/510k-Content) and in any device-specific guidance.
  10. Does your SE table identify similarities and differences in technological characteristics in a structured way?
  11. Do you make it clear why each of the differences does not pose a significant safety or effectiveness concern?
  12. Clinical performance data. Do the examples in the guidance suggest that you might need clinical evidence after all?
  13. If you are using an animal study, does it comply with applicable parts of GLP regulation (http://bit.ly/21-CFR-58)? This was already flagged in the RTA checklist (http://bit.ly/FDA-RTA-Policy). If the RTA reviewer can’t tick those boxes for question 39, then your submission won’t make it through the review.

Change #3: 510k Summary Template

Eleven pages, a quarter of the guidance document, are devoted to the 510k Summary, which will be posted on the FDA website. The guidance states that “FDA intends to verify the accuracy and completeness of the information included in a 510(k) Summary.” Your reviewer will have been so instructed. There is no change to the regulatory requirements for the Summary, but anyone who has combed through these while searching for a predicate will know that many Statements are incomplete. 

The FDA states that their focus on the Summary is in the interests of transparency, and they are making their point quite clearly in this guidance. As well as explaining each requirement, an example is provided. Therefore, I will be using Appendix C as a template for my 510k Summary.

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510k Technical File Conversion – 5 gaps to avoid

Posted by on September 2, 2014

Converting a technical file to a 510k submission is easy, but the 510k technical file conversion has 5 gaps you need to avoid.MDA techinical file blog 510k Technical File Conversion 5 gaps to avoidThis blog, 510k Technical File Conversion – 5 gaps to avoid, offers practical courses of action to consider related to this topic. Below are five parts of a technical file you are likely to be missing in your 510k documents:

  1. The biggest one first. Clinical evidence – The FDA states, “clinical data is not needed for most devices cleared by the 510(k) process.” The MDD 93/42/EEC (annex X) and proposed MD Regulation (Annex II) require a clinical evaluation to be performed and the evaluation report to be part of the technical file. Once formulated, the report becomes “clinical evidence” of the safety and performance of the medical device for demonstrating conformity with the relevant Essential Requirements (ER).

Here’s how to fill this gap using five steps offered by MEDDEV 2.7.1 Rev. 3:

  1. Identify the ERs requiring clinical support. (e.g., the device “shall not compromise the clinical condition or the safety of patients, or the safety and health of users” and “any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient.”
  2. Identify and “data pool” existing clinical data relevant to the device and its intended use. This should include any available post-marketing data on the same or similar device. But it may also comprise data from clinical trials or clinical use of a previous generation, or even a substantially similar device. Finally, if you are utilizing standard methodologies in your device, it may be possible to use data showing conformity to recognized standards.
  3. Evaluate the data to determine if it’s suitable for establishing the safety and performance of your device. Even some generally unusable studies may produce relevant data. It is important to perform this evaluation systematically. You might draw a chart listing the relevant ERs on the left and indicate the data source supporting or contradicting it to the right. The evaluation must objectively consider both positive and negative data.
  4. Generate any clinical data still needed. Consider methods other than a clinical trial for generating this missing data, e.g., “Data Pull” existing field data of the same or similar devices that may not yet have been ‘pulled’ through your PMS/RM Post-Production Infosystems. If data is unavailable, you may have no choice in generating it through a small-scale clinical trial. If so, keep it small, focused on the questions at hand, and statistically significant.
  5. “Bring all the clinical data together” to reach conclusions about your device’s clinical safety and performance. Essentially, conduct a benefit-risk analysis. Involve qualified team members: e.g., experts in medical conditions and device technology.

Now sum it up in a report.

  1. Essential requirements or General Safety and Performance Requirements Checklist – This central component of the technical file is based on Annex I of the three Medical Device Directives, or from the Proposed Regulation, respectively. There is no such review in a 510k.

Develop a checklist based on the principles in GHTF N68:2012 containing all of the following columns for each ER:

  • Applicable? – y/n; Is the requirement applicable? If not, why.
  • The method used to demonstrate conformity –harmonized standard, Common Technical Specification (CTS), etc…?
  • Specific Standard or CTS applied
  • Evidence of conformity  
  • –  the controlled document/s demonstrating fulfillment of the ER.
  1. Post-Market Clinical Follow-up (PMCF) Plan (and report) – The FDA requires PMS activities only once they have requested it from the manufacturer. A PMS plan then needs to be submitted. Manufacturers may not yet have formulated such a plan.

No worries. If you are performing your RM activities in compliance with ISO 14971, you will have an RMP or separate system, including a plan for observations, assessment, and action (ISO 14971:2007 § nine and TR 24971§ 4). Reference this in your technical file. What about the PMCF report?  Well, if you’ve performed post-market surveillance, develop one. Otherwise, see the next item below.

  1. Risk management report

While not required by the FDA in your 510k submission, you most likely have fulfilled this ISO 14971 requirement. Reference it in your technical file. Ensure you also include in the report a confirmation that appropriate methods are in place to obtain production and post-production information. If detailed enough, you can reference the report as a PMCF report (http://bit.ly/PMCFStudies), as well.

  1. Risk class/applicable classification rule (based on Annex VII (proposed EU regulations) or Annex IX (MDD)) – FDA defines Classes I through III, which are not parallel to Classes A-D in the proposed Regulation, nor the classes I, IIa, IIb or III of the current MDD.

Using either of the latter systems, identify the relevant rule, and classify your device—document in your technical file.

If you have finished your 510k technical file conversion, you might want to perform a technical file audit prior to submission to your notified body.

Avraham Harris is a GMP, GCP, and regulatory consultant and can be contacted at HARC.regulatoryaffairs@gmail.com.

 

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510k Submissions for Electrosurgical Devices-FDA’s 2 New Guidance Docs

Posted by on May 13, 2014

imgres 2 510k Submissions for Electrosurgical Devices FDAs 2 New Guidance Docs

For 510k submissions for electrosurgical devices, the author provides insight into FDA’s two new guidance documents, including how to document compliance.

A colleague asked me if I had noticed any changes to the FDA webpage summarizing the content requirements for a 510(k) submission (http://bit.ly/510k-Content). The page was last updated on March 18, 2014. However, when I compared the current page with a version I had saved in August 2013, I was able to confirm that there were no changes to the page, except for hyperlinks to the content referenced on the page. FDA released six new guidance documents in March, but two of these were specific to electrosurgical devices:

  1. Premarket Notification [510(k)] Submissions for Electrosurgical Devices for General Surgery (http://bit.ly/Electrosurgical-510k)
  2. Premarket Notification [510(k)] Submissions for Bipolar Electrosurgical Vessel Sealers for General Surgery (http://bit.ly/Bipolar-510k)

For those of you that are preparing 510(k) submissions, you may find the draft guidance documents for electrosurgical devices and bipolar electrosurgical vessel sealers to be quite helpful–even if you are are not submitting a 510(k) for these types of devices. These two draft guidance documents include specific recommendations for the content and format of the substantial equivalence table and performance data presented. Also, labeling requirements for the device include a long list of warnings that should be included in the IFU for this type of device.

Electrosurgical Devices for General Surgery

This guidance was released on March 24, 2014, and provides an update to the 510(k) submission requirements for electrosurgical devices in general. If you are preparing a 510(k) submission for this type of device, you should systematically verify and document how your submission complies with this guidance. Compliance with this guidance is not instead of but in addition to FDA guidance on the format and content of a 510(k) submission. Specifically, you should incorporate a table into one of the sections of the submission that lists each of the recommendations of the product-specific guidance document.

Bipolar Electrosurgical Vessel Sealers

This guidance was also released on March 24, 2014, and provides an update to the 510(k) submission requirements of bipolar electrosurgical vessel sealers for general surgery. This guidance includes all the same requirements as the guidance for Electrosurgical Devices, but the bipolar vessel sealing draft guidance also has one additional requirement. The draft guidance provides a prescriptive outline for a preclinical chronic animal study, including the minimum number of animals and the number of weeks post-procedure that the animals should be studied. In the past, the FDA has requested clinical studies in humans to demonstrate the long-term safety of the sealed vessels. Still, this draft guidance specifically states that human clinical studies are not required unless the device being submitted uses different “device technology and/or mechanism of action is significantly different when compared to the predicate.”

How to Document Compliance in Your 510(k) Submission

Medical Device Academy’s consulting team created a template for Section 9 of a traditional 510(k) submission that includes an overview document with the following sub-sections:

  1. FDA Special Controls
  2. FDA Device-Specific Guidance
  3. Voluntary Product Safety Standards
  4. FDA Recognized Standards

Sub-Section 1 of Medical Device Academy’s template for Section 9 of a traditional 510(k) submission includes a brief statement that there is no Special Controls guidance document for the product being submitted. For sub-section 2, we use a table identifying where each of the requirements of product-specific guidance documents can be located. If one of these two draft electrosurgical guidance documents is applicable to your device, we recommend including a table in Section 9 of your submission. For sub-sections 3 and 4, FDA requires that manufacturers complete a Standards Data Report for 510(k)s (FDA Form 3654, http://bit.ly/Form-FDA-3654) for each of the applicable test standards FDA recognizes. Failure to complete Form 3654 for 100% of the applicable standards FDA recognizes results in an immediate Refusal to Accept (RTA, http://bit.ly/FDA-RTA-Policy) letter.

58% of 510(k) submissions were rejected in 2013 during the initial 15-day administrative review. If you received already “Refusal to Accept” (RTA) letter, or you need help preparing your submission, please contact Glenn Melvin, Director of Business Development; by phone at (561) 308-3093 or by email at glenn@robertpackard.wpengine.com; to learn more about our consulting services, to schedule a call or to request a proposal.

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Why the FDA 510k Process Needs to Change Now: A Proposed Solution

Posted by on September 1, 2013

The author says three factors are accelerating the need for change to the current FDA 510k process and offers a proposed solution.

%name Why the FDA 510k Process Needs to Change Now: A Proposed SolutionWhen a company’s marketing literature tells you how a new device is different from competitor products, and the 510k summary for the same new device states that it is “substantially equivalent,” you can understand why the FDA may not fully support the 510k process for innovative, medium-risk devices.

There are many things wrong with the FDA 510k process, but the concept of using a predicate device and demonstrating equivalence is inherently a wrong approach for innovative devices. A preliminary report about the 510k process was released in 2010 (http://bit.ly/510kreport). The report states, “While the concept of ‘substantial equivalence to a predicate’ is generally reasonable, CDRH’s application of this standard has, in some instances, raised concerns.” Specifically, the use of predicate devices that were withdrawn from the market due to issues of safety or effectiveness, and the use of so-called “split predicates” may not ensure patient safety or device efficacy.

The FDA attempted to address issues identified in the report by issuing a draft guidance document for 510k submissions, but the industry hated it. The FDA has also gradually requested more clinical study data to demonstrate that the new device is substantially equivalent to the predicate device. This practice results in unexpected delays and much higher costs of regulatory approval. The FDA’s published guidance for 510k content (http://bit.ly/510kContent) indicates that “Clinical data is not needed for most devices cleared by the 510(k) process.” However, more than 10% of 510k submissions now require clinical data because the 510k for predicate devices included clinical data to demonstrate safety and effectiveness.

More recently, the FDA issued a draft guidance document for the De Novo process (http://bit.ly/DeNovoGuidance). The De Novo process allows the FDA to reset the submission requirements for devices that are not substantially equivalent and specify new requirements. The process has been used most for new In Vitro Diagnostic (IVD) products, and it is quite similar to the concept of Common Technical Specifications (CTS) introduced for IVD products in Europe.

Why the FDA 510k Process Needs to Change Now

The simultaneous confluence of three factors is accelerating the need for change in the 510k process. First, the cost of healthcare is skyrocketing. Therefore, patients and healthcare providers are desperately searching for less expensive treatment solutions. Second, insurance providers are demanding clinical evidence that new products are more effective than existing products that cost less. Third, evidence-based medicine is becoming mainstream. Physicians are no longer accepting the word of salespeople and marketing literature. Instead, physicians demand clinical data demonstrating that products are safe and effective. Users also want detailed information regarding patient selection criteria.

The collision of these three factors has exponentially increased the value and importance of clinical data. Still, only 10%+ of the 510k cleared devices to have clinical data at the time of product launch. Regulatory clearance to market a product is nearly useless if the product is not reimbursed, and users will not adopt its use. The modular Premarket Approval (PMA) process supports (http://bit.ly/PMAmethods) the need for preliminary safety data before clinical use, followed by a clinical study to demonstrate efficacy. However, 510k products are lower in risk and efficacy and can often be demonstrated with simulated use, animal testing, and cadavers.

As medical devices become more complex and innovative, bench-top testing and pre-clinical testing is not always adequate to demonstrate safety and efficacy for 510k products. Complex and innovative devices are extremely difficult to predict how the devices will interact with a broader population of users and patients, and it is difficult to predict the long-term effects of the devices—beyond the duration of a premarket, clinical study.

The PMA process requires premarket clinical data, but PMAs requires exponentially greater amounts of data than a 510k submission, and the FDA requires supplemental approval of almost every minor change (e.g., – changing a component supplier, or changing a test method). If the PMA process is too burdensome for most devices, and the 510k process is not adequate, what is the right process for the next generation of devices?

The De Novo process offers one solution, but it is still a premarket notification process. For the De Novo process to be useful for innovative devices, a Special Controls Guidance Document needs to include a requirement for both premarket clinical studies and Post-Market Surveillance (PMS).

Pilot Parallel FDA-CMS Review Process

In 2011, the FDA initiated a pilot program to allow companies to have PMA and CMS (http://bit.ly/Medicare-Medicaid) review processes occur in parallel (http://bit.ly/ParallelReview). The concept behind this pilot program is that the same clinical data must be reviewed for PMA approval and CMS reimbursement. If the pilot program is effective, products will be approved and reimbursed at the same time. However, this pilot program is only applicable to PMA products at this time. This program could be expanded to 510k products, where clinical data is presented as part of the application, but most 510k products do not warrant a clinical study.

Another Solution

The best tool to measure the safety of a new device is a clinical study, but U.S. clinical studies focus on demonstrating efficacy. Therefore, the FDA should consider using smaller clinical studies, without comparisons to predicate devices, to demonstrate safety rather than efficacy. This is the approach used by European Notified Bodies for medium and high-risk, innovative devices. This approach can also be integrated with a Special Controls Guidance Document for De Novo products.

For complex, innovative devices, the efficacy of the device is not reliably measured by clinical studies, because outcomes are highly dependent upon users. Premarket clinical studies can only estimate efficacy due to the small number of users. The lack of accurate efficacy predictability is why the FDA requires PMS for many PMA products. The best tool to measure efficacy is Post-Market Clinical Follow-up (PMCF) studies—not the premarket clinical studies the FDA uses to evaluate PMA applications. This is also the type of data that is required for CMS reimbursement and physician adoption.

Innovative devices are forcing regulations to evolve. The goal of regulators should be to produce a best-in-class method of evaluating which devices should be approved, reimbursed, and adopted as the standard of care.

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Three Ways to Streamline the 510k Process

Posted by on June 26, 2012

The author proposes three ways to streamline the 510k process through self surveys, scorecards, and modular submissions.

Modular submissions are already used for PMA submissions. Self-surveys and scorecards are tools that most companies utilize to evaluate vendors. Why not implement these solutions to make 510k reviews more efficient?

A few weeks ago, I posted a blog about the Triage pilot program at the FDA. I received some great comments by email, and this blog discusses this subject more in-depth with some specific ideas for streamlining the 510k process. Here’s the argument for considering these three proven methods:

Self-Surveys

In my previous posting about the Triage pilot program, I suggested using the existing FDA traditional 510k screening checklist and converting this into a similar “SmartForm.” Another way to think of this concept is by comparing it with a “Self-Survey.” Companies send Self-surveys to suppliers to gather information about the supplier as justification for approving them; Elsmar Cove has some discussion threads specific to the supplier self-surveys if you are unfamiliar with this method of torture. The critical step in the design of surveys is to require the submitter to provide references to procedures and forms, or to explain why something is not applicable. BSI uses this same strategy for its auditor combined checklists. Instead of checking “yes/no,” the auditor must reference a page in their audit notes where the objective evidence of conformity or nonconformity can be found. A submitter should fill in the checklist, rather than an FDA reviewer because this forces the submitter to verify that everything required is included. Canada has a similar requirement called a “submission traceability table” for Medical Device License Applications (see Appendix A). Self-surveys also replace some of the tedious searchings by a reviewer with cross-referencing work by the submitter. 

Scorecards

Another tool that supplier quality uses for supplier evaluations is the Scorecard: Elsmar Cove has a few discussion threads, including one with an example to download. For the 510 processes, I suggest developing scorecards for both the reviewer AND the submitter. The primary metrics for these scorecards would be on-time delivery and completeness of the submission for a submitter. “On-time delivery” requires advanced planning and communication of the submission with the FDA. This is important so that the FDA has adequate time before submission to identify the best reviewer(s) for the submission. The completeness of the submission should be 100% of a self-survey, SmartForm, or checklist used to prepare the submission. The primary metrics for the reviewer would be on-time completion and accuracy of the review.

The FDA already has target turn-around timescales for decisions (i.e., – 90 days), but there are different phases of review and multiple people the are involved in the reviews. Therefore, the measurement of reviewer time should be more granular. The accuracy of the reviewers should be validated by requiring all deficiencies to be re-evaluated by a peer or superior before involving the company. Submission sections without any findings should also be reviewed on a sampling basis as a double-check. Over time, the FDA should be able to use these scorecards to match up a reviewer with a submitter. It is critical that at least one of the parties is experienced, so we don’ t have the “blind leading the blind” situation. For those that are offended by the concept of a required second reviewer–get over it. Radiologists are periodically graded with images that are “red herrings.”

Modular Submissions

My third suggestion is to consider adopting some of the Premarket Approval (PMA) processes for the 510k process. In particular, pre-IDE meetings and modular submissions seem to be logical process improvements. There is typically one component of the submission that is a little behind the rest and can delay a submission. Under the current system, nothing is submitted or reviewed for a 510k, unless it is complete. However, it would enable companies to get new and improved products to market faster if submissions were modular. Validation, such as shelf-life and sterilization validation, is rarely the cause for a “Not Substantially Equivalent” (NSE) letter, but these tests are routinely the last few reports completed for submission.

Adopting a modular submission process for 510k would allow companies to submit sections of the submission as they are completed. This modular approach would alleviate the time pressure on both sides, and this proposed change should result in earlier product launch dates for the industry. The other component of this process is the pre-IDE Meeting. Before initiating a clinical study, companies will submit a plan for the study to the FDA. The intent is to obtain agreement on the validation testing that will be performed by the company–including the number of patients and the design of the clinical study. These meetings would also be valuable for 510k submissions where the company and the FDA need a forum to discuss what verification and validation testing will be required–especially for mixed-predicate devices and devices that are significantly different from a predicate device.

What do you think about these proposed changes to the 510k process?

Please share your own ideas for streaming the 510k process–including any comments regarding the FDA’s plans for change.

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FDA Approval Process: “Triage” for 510(k)

Posted by on June 2, 2012

The Triage program for 510(k) submissions is reviewed. The goal of this FDA approval process program is to reduce review time from 90 to 30 days.

Thursday, Congress voted 96 to 1 for a bill to increase FDA user fees. The rationale is that the FDA needs more funding to be strong enough to properly regulate foods, drugs, and medical devices. One of the commitments linked with this new funding is to shorten the review of 510(k) submissions. To this end, OIVD has created a new program called “Triage.” The goal of this program is to accelerate the review of specific traditional 510(k) submissions to 30 days instead of 90 days.

In theory, this pilot program will help some companies get their 510(k) clearance letter faster, but simultaneously, the FDA will be able to concentrate resources on high-risk 510(k) submissions. This entire strategy seems to be the opposite of triage. Triage involves sorting sick patients into three categories:

1) Those who are likely to live, regardless of what care they receive

2) Those who are likely to die, regardless of what care they receive

3) Those for whom immediate care might make a positive difference in their outcome

If we apply the triage analogy to 510(k) submissions, we see three categories:

1)      510(k) submissions that are likely to be approved, regardless of how much time the FDA spends

2)      510(k) submissions that are likely to be rejected, regardless of how much time the FDA spends

3)      510(k) submissions whose approval or rejection is not apparent, but the FDA’s earlier involvement in the design and development process would substantially improve review time.

The FDA’s “triage” program is intended to demonstrate improvement in the time required to approve medical devices by sorting submissions into two groups: group #1 above and group # 2/3 from above. This will make the numbers look good, but the FDA should be spending even less time on #2 than it spends on the #1 category of submissions. The FDA should also get involved in group #3 submissions much earlier.

FDA Approval Process

The types of submissions that need more FDA reviewer time are devices that are higher in risk and where special controls guidance documents and or ISO Standards have not already been established for performance and safety testing criteria (i.e., – Category #3 above). In these cases, when a company tries to obtain some feedback from the FDA, they are asked to request a pre-IDE meeting. The company will not be necessarily performing a clinical trial, but this is the only vehicle the FDA has for justifying the time it spends providing feedback on proposed verification and validation testing plans. The FDA needs to develop a new model that is ideally suited for 510(k) products where guidance and Standards do not exist. This would also have the effect of reducing the number of “Not Substantially Equivalent” (NSE) letters the FDA issues.

If a company is developing a device that already has an applicable special controls document or ISO Standard, then the 510(k) pathway should be well-defined without the FDA’s help. Unfortunately, there is no easy mechanism for ensuring compliance with these external standards. This type of submission would benefit from software-controlled submissions and or pre-screening of submissions by third-party reviewers. The Turbo 510(k) software tool could lend itself to software-controlled submissions, but a proliferation of the Turbo 510(k) has been limited.

Submitting a 510(k)

If a company does not submit a 510(k) with all the required elements of a guidance document, the submission should not be processed. Implementation of validated software tools for each 3-letter product code would prevent incomplete submissions. At the very least, companies should be required to provide a rationale for any sections of submission that are not applicable.

One example of a possible software solution is currently used by third-party auditors at BSI. BSI uses a software tool that will not allow the auditor to generate a final report unless all the required elements have been completed. The FDA could use the existing screening checklist and convert this into a similar “SmartForm.” If the submission does not have all the required elements of the checklist, the submission form could not be generated from the software. This forces the task of pre-screening reviews back upon the submitter with the aid of a validated software tool.

The most significant shortfall of the Triage program is the target product types. IVD devices are quite different from other device types. Each IVD has unique chemistry, and there are a limited number of Guidance documents for IVDs, and IVD submissions represent only 10-20% of all submissions. Orthopedic, cardiovascular, general/plastic surgery and radiology devices each represent more than 10% of the submissions, and collectively they represent half of the submissions. These types of devices also have both special controls documents and ISO Standards defining the design inputs for design verification. Therefore, these four device types would be a better choice for a pilot program to expedite reviews.

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