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FDA User Fee Increase for FY 2018 – Strategic Implications

This article identifies strategic implications of the FDA user fee increase for FY 2018 that was published by the FDA last week.

FY 2018 MDUFA Fees FDA User Fee Increase for FY 2018   Strategic Implications

You didn’t know the FDA user fee increased?

In August, the FDA publishes the new FDA user fee schedule for the next fiscal year, which begins on October 1. Last year the FDA published an updated small business guidance document in early August that included the fee schedule. This year, the release of the FY 2018 FDA user fee schedule was delayed until the end of August, because the re-authorization of user fees was not approved until August 18, 2017.

The MDUFA IV user fee schedule was negotiated in October of 2016, and the new user fee schedule proposed to increase the user fees to $999.5 million. That negotiated plan called for an increase in standard fees for 510k submissions while keeping small business fees lower. The final enacted MDUFA IV user fees follows this plan. There is a significant difference between PMA fees and 510k fees in the new fee schedule. There was a 33% increase for all PMA-related standard and small business fees. However, standard 510k fees increased by 125%, while small business fees for a 510k increased by 13%. The establishment registration fees increased by 37%, and there is still no discounted registration fee for small businesses. Finally, the biggest change is there will now be a fee for De Novo applications.

Implications of the De Novo FDA user fee increase

Congress authorized the MDUFA III fees in 2012 for five years, and there were no fees associated with De Novo applications. In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) also streamlined the De Novo application process. The purpose of having no fees, and for streamlining the process, was to encourage medical device innovation. However, only 40% of De Novo application reviews were completed within 150 days during 2015 and 2016. The balance of the applications required 200 to 600+ days to complete. Negotiations between the FDA and industry in 2016 resulted in an agreement to trade an increase in FDA user fees for a decrease in the review time required for 510k clearance. However, the FDA also committed to decreasing the De Novo application review time to less than 150 days as follows:

De Novo application decision goals for MDUFA IV 1024x118 FDA User Fee Increase for FY 2018   Strategic Implications
Unfortunately, the agreed FDA user fee for De Novo applications in MDUFA IV for FY 2018 are $93,229 as a standard fee and $23,307 for small businesses. During the past 5 years, during MDUFA III, companies that felt they had a potential De Novo application would try to persuade the FDA that a borderline 510k submission should be a De Novo application instead. However, under MDUFA IV you will be more likely to persuade the FDA that a borderline classification should be considered for a 510k submission instead of a De Novo application.

In addition, you should plan your De Novo application more carefully than you might have for a free application. Pre-submission meeting requests should always be submitted during the development process, and these pre-sub requests should be submitted at least 90 days prior to your design freeze. Special consideration should also be devoted to risk analysis and gathering preliminary data to demonstrate the effectiveness of the risk controls you select to ensure that the clinical benefits of your device outweigh the residual risks of the device after implementing risk controls. Ideally, you will gather enough evidence to create a draft special controls guidance document to submit to the FDA as a supplement to your pre-submission meeting.

If you are planning a De Novo application for FY 2018, you should expect your FDA reviewer to pay special attention to ensuring that there are no unnecessary delays in the review process. You should also monitor the FDA recent final guidance webpage for release of a final guidance document for De Novo applications. The draft guidance was released on August 14, 2014. Creating a final guidance will probably be priority for FY 2018.

Implications of the 510k FDA user fee increase

The standard FDA user fee for a 510k increased 125% from $4,690 to $10,566. However, the absolute dollar amount of a 510k submission is still less than cost of biocompatibility testing or sterilization validation. Therefore, the increase should not significantly decrease the number of submissions. However, the small business fee has only been increased by 13%. Therefore, if you are a small business (i.e., income < $100 million), you should complete an application for small business qualification as soon as you can (i.e., October 1, 2017) to make sure that you are eligible for the discounted fee when you submit your next 510k submission. If you need help preparing your small business qualification form, there will be a webinar on this topic Friday, September 8, 2017.

When you are planning a 510k submission, you should also determine if your device product classification is eligible for third party review. In the past, the increased cost of the third party review made submission of a 510k to a third party reviewer unattractive. However, the fees for third party reviews range from $9,000 to $12,000 typically. Therefore, its possible that there may be no difference in the fee for a third party review unless your company is a qualified small business.

Implications of establishment registration FDA user fee increase

The increase in the annual establishment registration fee is 37% for medical device firms to $4,624. If you are already registered as a medical device firm, you should increase your annual budget for the establishment registration fee accordingly. If you are about to launch a new product, remember that you are required to register and list your product within 30 days of distribution of your product. Therefore, if shipments are going to begin in September, you don’t need to register until October (i.e., after the start of the new fiscal year). Therefore, you may be able to avoid paying the FY 2017 establishment registration and only pay the FY 2018 establishment registration. This would not be the case for foreign firms that need to import the product prior to distribution.

What you can do about the FDA user fee increase now

You may not be able to change the user fee schedule for FY 2018, but there are three things you can do now to improve your situation. First, if you are a small business, you can speak to your accounting department and get them to provide a copy of the FY 2016 tax return so that you can complete the small business qualification form on October 1. Second, you should contact Regulatory Technology Services and the Third Party Review Group to obtain a quote for a third party review of your 510k submission instead of submitting directly to the FDA. Third, you should add a reminder to your calendar for August 1, 2018 to start reviewing the FDA website and other sources for a FY 2019 FDA user fee schedule.

Learning how to submit a small business qualification form

If you have not completed a small business qualification form before, you can learn how to prepare your application for small business qualification by registering for my webinar on Friday, September 8, 2017.

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

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 prior to actually completing the associated testing. The reason why you can write this section, prior to 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)

It is critical that you identify which category your sterilization process falls into, because the review process used by the FDA for each category of 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). 

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) prior to 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 novel, non-traditional sterilization processes, an 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 prior to issuing the 510k. The FDA published a draft guidance on this topic in 2008 that can be found at 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, and 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., prior to 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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510k Submission to the FDA (Case Study – Part 1)

This article is the first part of a two-part case study providing an overview of the pre-market notification process (i.e., 510k Submission) in order 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, but 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 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 use the US FDA Registration and Listing Database to identify the product classification simply by 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 a specific product classification. In the case of topical adhesives, the FDA has published 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 in an ISO Standard recognized by the US FDA. Since all the required performance testing 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 performance target for making a decision regarding clearance 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 will 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 specifically address unintentional bonding, 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 clearly 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™ (see picture below) is an example of a new applicator for a monomeric, 2-octyl cyanoacrylate.

fig.2 510K 510k Submission to the FDA (Case Study   Part 1)

My client has a similar applicator design to the pictures above, 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 product made by my client. In each of these protocols, the acceptance criteria is 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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510k Project Management-An Inside Look at Our Process

“510k Project Management-An Inside Look at Our Process” explains how the 510k Table of Contents is used for client submissions. A free download is provided. 

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

Despite all the perceived changes to the FDAs 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 (http://bit.ly/FDA-RTA-Policy) 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 are found in a 2005 guidance document titled, “Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 510(k)s” (http://bit.ly/510k-Content). To ensure that you don’t deviate from this required format, use a standardized template for the Table of Contents.

Overview

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 clearly identify the subject device of the submission, name of the section and the volume/document numbers. In addition to the templates our consulting team created, there are several FDA forms that 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 a 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, but 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

In order 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 https://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 (http://bit.ly/FDA-eCopy). Periodic updates are provided to the client via conference calls, but the client can view progress on the overall 510k submission project almost real-time by reviewing the 510k Table of Contents in spreadsheet form.

Coordinating Our Team

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), biocompatiblity (section 15) and pre-clinical animal studies (section 19). In fact, 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 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 important, 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 include 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 need 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 will also update our Table of Contents and send it to you if there are changes to the 510k requirements after the FDA has completed its retrospective review of the 2005 guidance document later this year (http://bit.ly/FY2015-Proposed-FDA-guidance).

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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Why Design Controls Are Important to 510k Submissions

why design 510k Why Design Controls Are Important to 510k Submissions

This blog explains how many sections of a 510k submission have a direct correlation to Design Controls.

If you are developing a medical device for the U.S. market, there is a decent chance you will need to prepare a 510(k) submission. Of course, there are some devices that do not require a submission, and also those that require a more involved PMA. But, if your medical device falls into the FDA Class II category, a 510(k) submission is required for market clearance.

Regardless of the device classification, Design Controls are a critical component to medical device product development. Design Controls demonstrate you have designed and developed a medical device that meets user needs, is safe and effective.

The relationship between Design Controls and regulatory submissions is strong. Design Controls are needed to ensure that you have the data to support your submission to the FDA for pre-market notification. A traditional FDA 510(k) submission contains 20 sections, and many of those sections are linked directly to Design Controls.

Indications for Use

The indications for use statement in a 510k submission describes the clinical application of a medical device. Before starting a medical device product development project, there must be a clinical need defined. This clinical need evolves into indications for use and results in User Needs. User needs describe what the end-user (including patient) expect the medical device to do. User needs are the pre-cursor to a medical device’s Design Inputs.

Declarations of Conformity

A 510k submission includes making declarations of conformity to any industry standard used during medical device product development. Some common standards include ISO 10993 (for biocompatability) and IEC 60601 (for electrical safety). Your medical device may require that you demonstrate compliance to other industry standards.

Any standards you reference as part of your medical device project have a direct relationship to Design Controls. Specifically, standards often specify requirements, acceptance criteria, and test methods. The contents of each standard must be translated directly into Design Inputs for your medical device or you must provide a justification of why the specific clause is not applicable. Additionally, declaring conformity to a standard means you will need to prove you meet the criteria within the standard. This is done via Design Verification activities.

Substantial Equivalence

The entire premise of a 510k submission is to demonstrate that your medical device is substantially equivalent to another medical device which has received FDA 510k market clearance. Doing so often requires head to head testing and other activities to demonstrate your product is equivalent to a predicate device. Activities to support substantial equivalence are often captured as Design Verification activities.

Proposed Labeling

The proposed labeling is included with a 510k submission. Labeling includes the labels applied directly to the product and packaging, as well as instructions for use and user manuals. Labeling is part of the Design Outputs captured during product development. Labeling also tells the user about residual risks that design controls were not able to completely eliminate.

Sterilization & Shelf Life

If your medical device requires sterilization, you must provide details regarding sterilization methods and specifications with your 510k submission. Sterilization methods and specifications are Design Outputs. Expect to also provide a sterilization validation protocol, as well as results, with your 510k. These are Design Verification activities.

The same is true with shelf life activities. Shelf life definitions are defined as Design Outputs, usually via product labeling. These labeling claims of shelf life must subsequently be verified during design verification.

Biocompatibility

If your product has contact with a patient and/or end-user, you need to demonstrate biocompatibility within your 510(k) submission. Biocompatibility requirements must be defined as Design Inputs, and the Design Verification data must include evidence of meeting these requirements.

Software

If your medical device includes software, there is quite a bit of documentation you are expected to provide as part of a 510k submission. Things like Software Requirements Specifications (part of Design Inputs), Software Design Specifications (part of Design Outputs), and Software Verification Test Plan & Results (part of Design Verification). Depending upon the level of risk, risk management documentation may also be required for devices involving software.

Electromagnetic Compatibility

If your medical device includes electronics, you need to demonstrate electromagnetic compatibility and overall electrical safety within the 510k. This involves IEC 60601 and all the applicable parts of this standard to your product. Electrical requirements should be specified as Design Inputs. All the test results are Design Verification activities.

Performance Testing

All bench, animal, and clinical performance testing must be provided with your 510k submission. Required performance testing is specified for some device classifications with documented Special Controls Guidance Documents, while other device classifications require only that you provide performance testing demonstrating that the device in your submission is equivalent to the predicate device. This performance testing must be specified as verification and validation testing in your Design Plan.

 

jon d speer Why Design Controls Are Important to 510k SubmissionsJon Speer is a medical device veteran with more than 16 years experience. Jon specializes in helping medical device start-up companies with design project management. His experience with start-ups gave him the idea to develop a software solution to help companies document Design Controls. If you are interested in learning more about the software solution, greenlight.guru, you can find him on Google+, Twitter, and LinkedIn.

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

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 totally 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 certain cases, 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 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 in order 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, but only 10%+ of the 510k cleared devices 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 prior to 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 pre-market, clinical study.

The PMA process requires pre-market clinical data, but PMAs require 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 pre-market notification process. In order for the De Novo process to be effective for innovative devices, a Special Controls Guidance Document needs to include a requirement for both pre-market 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. Pre-market 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 pre-market 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.

Posted in: 510(k)

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Three Ways to Streamline the 510k Process

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.” Self-surveys are sent by companies to suppliers in order 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. This same strategy is used by BSI for their 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 searching 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 purpose of the 510 process, 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 prior to 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 prior to 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 an “Not Substantially Equivalent” (NSE) letter, but these tests are routinely the last few reports completed for a 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 industry. The other component of this process is the pre-IDE Meeting. Prior to 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.

Posted in: 510(k)

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

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 in order 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 certain 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 clear, 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 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 a 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 biggest shortfall of the Triage program is the target product types. IVD devices are quite different from other device types. Each IVD has unique chemistry, 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.

Posted in: 510(k)

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