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Three (3) important technical file and 510k submission differences

This article summarizes the three (3) important technical file and 510k submission differences: 1) the risk management file, 2) the clinical evaluation report, and 3) the post-market clinical follow-up report.

3 different apples Three (3) important technical file and 510k submission differences

3 important technical file and 510k submission differences

ISO 14971 requires a risk management file whether you are selling a medical device in the EU or the USA, but the US FDA doesn’t require that you submit a risk management file as part of the 510k submission. If you design and develop a medical device with software, you must submit a risk analysis if the software has a moderate level of concern or higher. However, the risk analysis is only a small portion of a risk management file.

Only 10-15% of 510k submissions require clinical studies, but 100% of medical devices with CE Marking require a clinical evaluation report (CER) as an essential requirement in the technical file. The clinical evaluation report (CER) is essential requirement (ER) 6a in Annex I of the Medical Device Directive (MDD). Even class 1 devices that are non-sterile and have no measuring function require a clinical evaluation report (CER). Yes, even adhesive tape with a CE Mark requires a clinical evaluation report in the technical file.

Annex X, 1.1c of the Medical Device Directive (MDD) requires that medical device manufacturers perform a post-market clinical follow-up (PMCF) study or provide a justification for not conducting a post-market clinical follow-up (PMCF) study. In the past, companies attempted to claim that their device is equivalent to other medical devices and therefore a post-market clinical follow-up (PMCF) study is not required. However, in January 2012 a guidance document (MEDDEV 2.12/2) was published to provide guidance regarding when a PMCF study needs to be conducted. This guidance makes it clear that PMCF studies are required for many devices–regardless of equivalence to other devices already on the market.

Risk management file for technical file and 510k submission

The FDA only requires documentation of risk management in a 510k submission if the product contains software and the risk is at least a “moderate concern.” Even though you are required to perform risk analysis, a knee implant would not require submission of the risk analysis with the 510k. If a product is already 510k cleared, you may be surprised to receive audit nonconformities related to your risk management documentation for CE Marking. The most common deficiencies with a risk management file are:

  1. compliant with ISO 14971:2007 instead of EN ISO 14971:2012
  2. reduction of risks as low as reasonably practicable (ALARP) instead of reducing risks as far as possible (AFAP)
  3. reducing risks by notifying users and patients of residual risks in the IFU
  4. only addressing unacceptable risks with risk controls instead of all risks–including negligible risks

If you are looking for a risk management procedure, please click here. You might also be interested in my previous blog about preparing a risk management file.

Clinical evaluation report (CER) for technical file and 510k submission

The FDA does not require a clinical evaluation report (CER), and up until 2010 only some CE Marked products were required to provide a clinical evaluation report (CER). In 2010 the Medical Device Directive (MDD) was revised and now a clinical evaluation report (CER) is a general requirement for all medical devices (i.e., Essential Requirement 6a). This requirement can be met by performing a clinical study or by performing a literature review. Since 510k devices only require a clinical study 10-15% of the time, it is unusual for European Class 1, Class IIa and Class IIb devices to have clinical studies. This also means that very few clinical studies are identified in literature reviews of these low and medium risk devices.

The most common problem with the clinical evaluation reports (CERs) is that the manufacturer did not use a pre-approved protocol for the literature search. Other common problems include an absence of documented qualifications for the person performing the clinical evaluation and failure to include a copy of the articles reviewed in the clinical evaluation report (CER). These requirements are outlined in MEDDEV 2.7/1, but the amount of work required to perform a clinical evaluation that meets these requirements can take 80 hours to complete.

If you are looking for a procedure and literature search protocol for preparing a clinical evaluation report (CER), please click here. You might also be interested in my previous blog about preparing a clinical evaluation report (CER).

Post-Market Surveillance (PMS) & Post-Market Clinical Follow-up (PMCF) Studies for technical file and 510k submission

Post-market clinical follow-up (PMCF) is only required for the highest risk devices by the FDA. For CE Marking, however, all product families are required to have evidence of post-market clinical follow-up (PMCF) studies or a justification for why post-market clinical follow-up (PMCF) is not required. The biggest mistake I see is that manufacturers refer to their post-market surveillance (PMS) procedure as the post-market surveillance (PMS) plan for their product family, and they say that they do not need to perform post-market clinical follow-up (PMCF) study because the device is substantially equivalent to several other devices on the market.

Manufacturers need to have a post-market surveillance (PMS) plan that is specific to a product or family of products. The post-market surveillance (PMS) procedure needs to be updated to identify the frequency and product-specific nature of post-market surveillance (PMS) for each product family or a separate document needs to be created for each product family. For devices that are high-risk, implantable or devices that have innovative characteristics the manufacturer will need to perform some post-market clinical follow-up (PMCF) studies. Even products with clinical studies might require post-market clinical follow-up (PMCF), because changes to the device, accessories and range of sizes may not be covered by the clinical studies. MEDDEV 2.12/2 provides guidance on the requirements for post-market clinical follow-up (PMCF) studies, but most companies manufacturing moderate risk devices do not have experience obtaining patient consent to access medical records in order to collect post-market clinical follow-up (PMCF) data–such as postoperative imaging.

Procedures & Webinars

If you are looking for a procedure for post-market surveillance (PMS), please click here. If you are interested in learning more about post-market surveillance and post-market clinical follow-up (PMCF) studies, we also have a webinar on this topic.

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How to create a template for 510k submission device description

This article explains how to create a template for 510k submission device description (i.e., Section 11). The template addresses each of the requirements of a device description in the FDA refusal to accept (RTA) guidance document. The template also serves as a summary technical document (STED) for submission to a Notified Body for CE Marking.

Screenshot 2015 11 04 at 8.41.36 AM How to create a template for 510k submission device description

You would think that it’s really hard to screw up the device description, but the FDA screening reviewer is completing a new refusal to accept (RTA) checklist (effective October 1, 2015). That checklist has specific requirements for a device description. If you copy the device description from your draft IFU, then you will probably receive an RTA letter on Day 15 of the RTA screening process. The review “clock” is reset to zero, and you have to revise your device description and re-submit.

There are four specific requirements (questions 9-12) in section “B” of the RTA checklist which is titled “Device Description.” In addition to this, there are similar requirements for inclusion in a device description for technical file and design dossier submissions to Notified Bodies. Rather than creating two different device description documents, I prefer to create a template that addresses each of the regulatory requirements in a single controlled document. Therefore, I created a template for the 510k submission device description with the following headings for Section 11 of the 510k submission:

  1. Product or trade name
  2. General description—including intended purpose. The general description must be consistent with the device description in the labeling, and this section of the document is intended to address section 10 of the refusal to accept (RTA) checklist.
  3. A list and description of each device for which a 510(k) clearance is requested in the submission. The list may refer to models, part numbers, various sizes, etc. This section of the document is intended to address section 11c of the refusal to accept (RTA) checklist. It may be helpful to combine this section with section 3 of the template providing a table with UDI device identifier for each product listed.
  4. UDI device identifier(s)—if available.
  5. Intended patient population, medical condition to be diagnosed and/or treated and other considerations such as patient selection criteria.
  6. Principles of operation of the device. This section of the document is intended to address section 11a of the refusal to accept (RTA) checklist.
  7. A description of proposed conditions of use, such as surgical technique for implants; anatomical location of use; user interface; how the device interacts with other devices; and/or how the device interacts with the patient. This section of the document is intended to address section 11b of the refusal to accept (RTA) checklist.
  8. Risk class and applicable classification rule according to Annex VII (proposed EU regulations) or Annex IX (MDD). For this section I will cross-reference to a controlled document that includes the complete classification rationale, while this section only includes the classification and the applicable rule(s).
  9. Explanation of novel features (be careful, this is a regulatory document and not a marketing document).
  10. Description of components, accessories, other medical devices and other products that are not medical devices, which are intended to be used in combination with the device. Each component/accessory that was part of a previous submission should be identified by the 510k number. Any component(s)/accessory(s) that have not received prior clearance should also be identified. Sometimes a side-by-side table for USA and EU markets is needed for accessories where different accessories are used in different markets. This section of the document is intended to address section 12a, b and c of the refusal to accept (RTA) checklist.
  11. Description or complete list of the various configurations/variants of the device that will be available
  12. General description of the key functional elements, formulation, composition, and functionality—including labelled pictorial representations (e.g. diagrams, photographs, and drawings)
  13. Raw materials incorporated into key functional elements and those making direct contact with the human body or indirect contact with the body
  14. Technical Specifications of the device and any variants and accessories that would typically appear in the product specification made available to the user, e.g., in brochures, catalogues and the like.
  15. Representative engineering drawing(s), schematics, illustrations, photos and/or figures of the device. This section of the document is intended to address section 11d of the refusal to accept (RTA) checklist.
  16. Reference to similar and previous generations of the device. It is important to make sure these devices are included in the clinical evaluation report and if you are submitting a 510k submission you want to make sure that any devices are registered and listed with the US FDA in the same product category. For a device with multiple predicates, it may be necessary to create a table that organizes the “similar” devices by intended use and technological characteristics.
  17. Requirements specific to special controls guidance document. This section of the template is intended to address section 9 of the refusal to accept (RTA) checklist.

The last section of the device description STED is for any unique requirements specific to the special controls guidance document for the product classification I am working on. However, most of the requirements for a device description are met by the previous items in my outline. Therefore, I create a table that outlines each of the requirements of the special controls guidance document and I provide a cross reference to the section of the outline that includes this requirement. If there are requirements not covered elsewhere in the document, I address the requirement in the table itself. If there is no special controls guidance document, then I state that no special controls guidance document exists for the product.

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Biocompatibility for 510k Submissions vs CE Marking

asr 1 Biocompatibility for 510k Submissions vs CE Marking
Titanium is not biocompatible?!

This article compares the different documentation requirements of biocompatibility for 510k submissions with a technical file submission for CE Marking.

A couple of my clients recently received requests for additional information as part of their technical file submission for CE Marking. Both clients had titanium implants, and they submitted exactly the same justification of biocompatibility for 510k submissions as they were now submitting for their technical file. They were providing a one paragraph description of materials used and referencing the ASTM specification for implant-grade titanium. Both clients already had CE Marking for similar devices, and the wording of the justification for not conducting biocompatibility testing on the full device was identical to the previous submissions.

“Justifications are no longer permitted”

One of my clients questioned whether there was a new EN standard for implant-grade titanium that they might need to comply with. The other client was told by their auditor that the Notified Body would no longer accept justifications for not conducting biocompatibility testing.

On behalf of my clients I scheduled a meeting with their Notified Body to obtain clarification and to make sure that the policies for documentation of biocompatibility had not changed. The Notified Body had three important points to make:

  1. Justifications are PERMITTED as it states in EN ISO 10993-1:2009
  2. Competent Authorities noticed that some of the justifications accepted in the past were not sufficient
  3. What the FDA accepts for biocompatibility for 510k submissions is not sufficient for a technical file

FDA requirements of biocompatibility for 510k submissions

In 1995, the FDA published a biocompatibility guidance document. That guidance document includes a decision tree that asks a series of questions related to biocompatibility for 510k submissions that is intended to help manufacturers determine which biocompatiblity testing may be required for 510k submission of their new or modified device. The following questions are the critical items covered in that decision tree: 

  • Is the material the same as a marketed device?
  • Same manufacturing process?
  • Same chemical composition?
  • Same body contact?
  • Same sterilization method?
  • Is the material metal, metal alloy or ceramic?
  • Does it contain any toxic substances (e.g., Pb, Ni, Cd, Zr)?
  • Master file has acceptable toxicology data?

In the past, I recommended that clients with titanium implants prepare section 15 of their 510k submissions by answering each of the questions above. 99% of the time, the predicate device is substantially equivalent to the 510k submission device with regard to the first five questions. Except in the case of coated implants, their was seldom a Device Master File to reference and the metal was compliant with the ASTM standard for titanium implants–including the concentrations of heavy metals.

For other medical devices that were not made of just titanium or some other implant-grade metal, the manufacturer was forced into to conducting biocompatiblity testing. In these cases, I directed the clients to follow the biocompatibility testing matrix published by the FDA.

New Draft Biocompatibility Guidance from the FDA

In 2013, the FDA published a FDA 2013 draft guidance document for biocompatibility with additional requirements for biocompatibility documentation and testing. The newer draft guidance appears to be the current expectation of the agency for 510k submissions, but the draft guidance has not been finalized yet.

The new 2013 draft guidance document from the FDA indicates that biocompatiblity testing reports must be provided with 510k submissions instead of merely summarizing the testing performed. The FDA clarifies in the draft that materials will not be evaluated alone, and the full device must be evaluated for biocompatibility instead. The FDA also specifies that the device evaluation must be for a sterilized device if the device is intended to be delivered in a sterile state to users/patients. This draft incorporates new ideas regarding toxic chemicals, such as colorants. The FDA also suggests that manufacturers discuss their testing plans with the FDA before starting the biocompatibility testing.

Despite the changes proposed in the 2013 draft guidance, there are no changes to the requirements of biocompatibility for 510k submissions if the device is a metallic implant that is substantially equivalent to a predicate device.

Technical File Differences for Bioiocompatibility

In theory, there should be very few differences between biocompatibility for 510k submissions and technical file requirements for CE Marking, because the FDA recognizes ISO 10993-1:2009, and the content of the standard is nearly identical to the European national version of the standard. For European CE Marking, the expectation is for the technical file to include documentation of conformity with the current state of the art for biocompatibility (i.e., EN ISO 10993-1:2009). Summary Technical Documentation (STED) is preferred by Notified Bodies in order to reduce time and costs associated with the review of the technical documentation.

A STED that explains how your biocompatibility evaluation conforms to a harmonized European Standard is quite different from a justification based upon substantial equivalence. Notified Bodies expect you to review each of elements of the harmonized standard and explain how you address it in the STED. In Clause 7 of EN ISO 10993-1:2009, there are seven elements recommended for a biological safety assessment:

  1. the strategy and program content for the biological evaluation of the medical device;
  2. the criteria for determining the acceptability of the material for the intended purpose, in line with the risk management plan;
  3. the adequacy of the material characterization;
  4. the rationale for selection and/or waiving of tests;
  5. the interpretation of existing data and results of testing;
  6. the need for any additional data to complete the biological evaluation; and
  7. overall biological safety conclusions for the medical device.

The fourth element of the biological safety assessment will certainly include a reference to the implant-grade titanium that you are using. However, you also must address additional questions that are posed in Figure 1 of the standard. Questions that should be addressed in your biological safety assessment include:

  1. Are there any additives, contaminants and residues remaining on the device?
  2. Are there any substances leachable from the device? 
  3. Are there any degradation components of the device?
  4. Are there other components and how might they interact with final product?
  5. What are the properties and characteristics of the final product?

 If you conducted a cleaning validation, you need to reference that process validation report. If you conducted testing of EO residuals, you need to reference the ISO 10993-7 test report.

The message the Notified Bodies are sending you is that they agree that implant-grade titanium is biocompatible, but you need to systematically write a justification for not conducting the testing in accordance with the EN standard and you have to cross-reference to your objective evidence throughout the STED. 

Posted in: 510(k), CE Marking

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5 Alternatives When You Can’t Find a Predicate Device

This article summarizes five alternatives that medical device manufacturers have for regulatory approval in the US when a 510k submission predicate device cannot be identified.

success and failure choices 5 Alternatives When You Can’t Find a Predicate Device

Choosing the best 510k submission predicate device is critical to success or failure.

The premise behind the FDA 510k regulation is that your new device is substantially equivalent to another device (i.e., predicate device) that is already on the market. Therefore, you only need to submit a premarket notification to the FDA instead of a premarket approval (PMA) submission. Most 510k submissions reference a similar device manufactured by a competitor, but what do you do when you can’t find a predicate device?

Your 5 Options

  1. Conduct a Clinical Study and Prepare a PMA Submission = $$$ + 2 years min.
  2. Prepare a DeNovo Submission = 120 days instead of 90 days
  3. Submit a 510k with Your Best, Poor Choice & Expect One of Two Responses: Refusal to Accept (RTA) or Not Substantially Equivalent (NSE)
  4. Request a Pre-Sub Meeting with the FDA = 60-day Delay at Front of Project
  5. Submit a 513(g) Request to the FDA = $ + 60-day Delay at Front of Project

Option 1 – Conduct a Clinical Study & Prepare a PMA

If you cannot identify a predicate device, you may need to conduct a clinical study to demonstrate that your new device is safe and efficacious. Some devices even require an investigational device exemption (IDE) approval from the FDA if the risks of the device are significant. If your device presents significant risks, it is likely that the De Novo process (Option #2 below) will not be an option and the device will be considered a Class III device by the FDA. In this case, the fastest pathway to regulatory approval is a modular PMA submission. The minimum timeline for this type of submission is typically two years, and the FDA user fee for a PMA submission is very high–unless you are a start-up company and this is your first product. The following FDA webpage summarizes the process for a modular PMA:

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm089767.pdf

Option 2 – Prepare a De Novo Submission

Originally the De Novo process was created with IVD products in mind where the technological characteristics are nearly identical between two devices, but the intended use is different (i.e., device is used to diagnose a different disease). The problem with the original process is that you had to submit a 510k and have it rejected before you were allowed to submit a De Novo application. Now the De Novo process allows two pathways. A company can submit a 510k, have it rejected with a “not substantially equivalent” (NSE) letter and then submit a De Novo application. The new option allows a company to skip the initial 510k submission and submit a De Novo application first. This extends the decision time from 90 days to 120 days, but the previous option took even longer.
The following FDA webpage has the De Novo draft guidance document that was released last year:

http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm273902.htm

The following FDA webpage summarizes all the De Novo applications that have been reviewed and approved recently:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm232269.htm

Option 3 – Submit a 510k Anyway

This is probably not your best approach, but sometimes it’s worth a shot to see what the FDA will say instead of waiting to schedule a pre-submission meeting and this approach doesn’t eliminate option #2. There are two likely outcomes from this approach. First, the reviewer screening your 510k submission during the 15-day, refusal to accept (RTA) process will determine that you have not selected a suitable predicate device and you will receive an RTA letter. In this case you have an answer in just 15 days. You should never accept your first RTA letter. You should make the requested changes the reviewer indicates and re-submit. The FDA’s goal is to have all submissions make it through the RTA process on the second try. Therefore, you might have more success on the second try with another predicate or just by fixing other problems the reviewer identified.

The other possible outcome of this approach is that you will make it through the RTA process, but your submission will be determined to be NSE. In this case, you will received an NSE letter from the FDA and it will suggest options–typically a PMA or a De Novo submission. If a De Novo submission is a good option it will be stated in the letter.

Option 4 – Request a Pre-Submission Meeting

If you are not able to identify a suitable predicate you might consider preparing a classification rationale and select a potential predicate. Then this information can be summarized in a pre-submission meeting request to the FDA. The FDA will respond within 75-90 days from your submission. If you are still developing your device and you have not started any performance testing, then this option may be your best approach. I recently recorded a live webinar on the topic of pre-submission meetings for 510k submissions:

http://robertpackard.wpengine.com/live-webinar-on-510k-submissions-fda-pre-sub-meetings/

The webinar includes specific dos and don’ts for for pre-submission meetings. There is also a final guidance for the pre-submission program that was released last year on February 18, 2014:

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance//guidancedocuments/ucm311176.pdf.

Option 5 – Submit a 513(g) Application

When a company has difficulty identifying a 510k submission predicate device, the FDA recommendation is to submit a 513(g) application. As I indicated in a past blog (http://robertpackard.wpengine.com/fda-device-classification/), the 513(g) process may not be your best choice for two reasons. First, the 513(g) process takes 60 days before the FDA provides a response. Second, the 513(g) process has a user fee that is higher than hiring a consultant to do the same research. Since the FDA 513(g) response is “non-binding”, the FDA’s opinion doesn’t necessarily hold any more weight than an experienced consultant. Therefore, paying a consultant to do the research and then requesting a pre-sub meeting is probably a better approach, but the timeline for a 513(g) submission is slightly shorter.

Do You Still Have Questions?

I will be recording a live webinar overview of the 510k submission process next Thursday, June 4 at Noon Eastern, but we have already sold-out 1,000 registration spots. Therefore, we are now offering a second webinar earlier in the day on this topic:

http://robertpackard.wpengine.com/510k-submission-predicate-device/

This second webinar starts at 9am Eastern, and it might be a better time for European companies that have questions specific to 510k submissions.

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Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

This article explains how to reduce your workload by at least 35% if you integrate your two project plans for a 510k submission and CE Marking into one comprehensive regulatory plan.

510k submission and CE Marking Combining a 510k Submission with CE Marking: 9 Sections that are Duplicated

My first medical device regulatory submission was for CE Marking, while my second regulatory submission was for a 510k submission of the same product. This is a very common path for medical device regulatory submissions, but it is also an inefficient path. If you know that you will be submitting both types of documents, then you should plan for this from the start and reduce your workload by at least 35%.

The reason why you can easily reduce your workload is that there are nine key sections in both submissions that are very similar. Therefore, you can write the content for those nine sections in such as way that the content can be used for your 510k submission and CE Marking.

9 Sections are Duplicates

Here are the nine key sections that the two types of regulatory submissions have in common:

  1. Device Description
  2. Labeling
  3. Sterilization & Shelf-Life
  4. Biocompatibility
  5. Software
  6. EMC/Electrical Safety
  7. Bench Testing
  8. Animal Testing
  9. Clinical Testing

There are 20 sections required by the FDA for a Traditional 510k submission, but often some of the sections are boilerplating and other sections are not applicable to the device being submitted. A few sections are unique to a 510k submission, such as:

  • Substantial Equivalence
  • 510(k) Summary
  • User Fee Cover Sheet Form 3601 & Submission Cover Sheet Form 3514
  • Declarations of Conformity on Form 3654
  • Table of Contents

Technical Files for CE Marking also have a few unique sections, such as:

  • Essential Requirements Checklist
  • Classification Rationale
  • CE Marking Application to Notified Body
  • Declaration of Conformity
  • Table of Contents

How to Construct Your Plan

In one of my previous blogs I explained how I use the 510k Table of Contents as a project management tool for a 510k submission. You can do the same when you are constructing a combined plan for a 510k submission and CE Marking. The first step is to create the same kind of project management tool I use for a 510k submission (i.e., a Table of Contents) to manage your CE Marking Technical File. I recommend preparing your Technical File in accordance with the GHTF guidance document released by study group 1: N011:2008. This guidance mirrors the format that will be required in Annex III of the new European Medical Device Regulations that should be released next spring. I do not recommend using the NB-MED 2.5.1/rec 5 guidance document. Even though the content is similar to the GHTF guidance, the format is quite different. After I have two separate project plans organized in accordance with the Table of Contents, then I merge the two plans on a spreadsheet and consolidate the duplicate sections.

Scheduling Tasks & Project Management

If you are going to outsource sections of either submission, these 9 sections should be written and reviewed by someone that is familiar with both types of submissions. The headers and footers will be unique to the type of submission, but I write the text in Google Docs without formating for ease of sharing and so I can use my Chromebook.

If you have an in-house team that prepares your 510k submissions and Technical Files, you might consider training the people responsible for each section on the requirements for each type of submission. This eliminates rewriting and reformatting later. I like to assign who is writing each section in a separate column of my Table of Contents planning tool. Then I will sort the sections by expected date of completion. All the safety and performance testing, and any sections requiring validation, will typically be finished at the end of the project. Therefore, it is important to dedicate unique resources to those sections rather than asking one person to write several of those sections. You also will want to make sure any supporting documentation they need is completed early so that the project’s critical path doesn’t change. I typically use a Chromebook spreadsheet for all of this, because 20+ sections is just too few tasks to warrant the use of Microsoft Project or some other Gantt Chart planning tool. If you keep it simple, more of your team will read it and update it frequently.

RA Consulting Tip

I have several PCs (laptops and desktops of various vintages), but nothing is faster for writing plain text than a Chromebook. Then I export documents to Word format and work on tables and formatting of the information as needed. I can also jump on any computer with an internet connection and work on my documents. This enables me to travel very light when I need to. If you are a tablet user, there are some other solutions I prefer–such as Evernote.

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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Comparing HUD, HDE and 510k Submissions

This article compares the differences between the regulatory pathways for an HDE and 510k submission. The article also explains how the Humanitarian Use Device (HUD) designation  and Humanitarian Device Exemption (HDE) compare.

HUD Designation 300x229 Comparing HUD, HDE and 510k Submissions

Last year the FDA released a draft guidance document explaining the regulatory process for applying for an HDE:
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm389154.htm

HUD designation is for product that affect less than 4,000 patients per year in the United States. There are three steps required before a HUD may be used at a user facility:

  1. HUD Designation Request to Office of Orphan Products Development (OOPD)
  2. HDE Application to Center for Devices and Radiological Health (CDRH)
  3. Investigational Review Board (IRB) approval of using the HUD

Note: The above regulatory pathway may not apply to combination products. In the case of combination products, you should contact the Office of Combination Products (OCP).

Major Differences

  • Unlike the 510k process, HDE approval is device approval rather than “clearance” for marketing and distribution.
  • If another equivalent (actual term used is “comparable”) device is already being legally marketed, then the FDA may not approve an HDE application. In contrast, the first requirement for determination of substantial equivalence of a subject device for a 510k submission is that the predicate device must be a legally marketed device that is equivalent.
  • There are no user fees for an HDE application, while 510k submissions generally are subject to user fees; pediatric-only products are an exception to the requirement for 510k user fees.
  • There is no requirement to demonstrate effectiveness of devices in an HDE application. Instead, devices approved for HDE must provide an acceptable risk/benefit analysis.
  • HDE approved devices are not generally eligible to make a profit. In fact, any device that a manufacturer intends to sell for more than $250 requires a report issued by an independent public accountant.
  • IRB approval for use of a HUD approved for marketing is required, but the IRB approval is not for a clinical study and IRB approval is not required in the case of an emergency.

The FDA guidance document also explains how HDE approval is different from a pre-market approval (PMA).

 

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When Can I Use a Second 510k Predicate?

This article describes when you can use a second 510k predicate for demonstrating substantial equivalence of your subject device in a 510k submission.

Split Predicate 300x188 When Can I Use a Second 510k Predicate?

Recently a client questioned me about the use of a secondary predicate in a 510k submission that I was preparing. They were under the impression that only one predicate was allowed for a 510k submission, because the FDA considers the two predicate devices to be a “split predicate.”  About half of the 510k submissions I helped prepare in the past year have used a secondary predicate, and all of the submissions have been cleared so far. When is a second 510k predicate allowed?

The FDA released a new guidance document that explains how to demonstrate substantial equivalence. The guidance document includes a new decision tree that summarizes each of the six questions that 510k reviewers are required to answer in the process of evaluating your 510k submission for substantial equivalence. The evidence of substantial equivalence must be summarized in Section 12 of your submission, and the guidance document reviews the content that should be provided.

Substantial equivalence is evaluated against a predicate device or multiple predicates. In order to be considered substantially equivalent, the subject device of your 510k submission must have the same intended use AND the same technological characteristics as the predicate device. Therefore, you cannot use a two different predicates if one predicate has the same intended use (but different technological characteristics) and the second predicate has the same technological characteristics (but a different intended use). This does not prohibit you from using a secondary predicate, but you must meet the requirements of this guidance document in order receive 510k clearance. In fact, the guidance document reviews five examples of multiple predicates being used correctly to demonstrate substantial equivalence.

When you are trying to use multiple predicate devices to demonstrate substantial equivalence to your subject device in a 510k submission, you have three options for the correct use of multiple predicate devices:

  1. Two predicates with different technological characteristics, but the same intended use.
  2. A device with more than one intended use.
  3. A device with more than one indication under the same intended use.

If you use “option 1”, then your subject device must have the technological characteristics of both predicate devices. For example your device has Bluetooth capability and it uses infrared technology to measure temperature, while one of the two predicates has Bluetooth but uses a thermistor and the other predicate uses infrared measurement but does not have Bluetooth.

If you use “option 2”, you are really combining the features of two different devices into one device. For example, one predicate device is used to measure temperature and the other predicate device is used to measure blood pressure. Your device, however, is able to perform both functions. You might have chosen another multi-parameter monitor on the market as your predicate, however, you may not be able to do that if none of the multi-parameter monitors have the same combination of intended uses and technological characteristics. This scenario is quite common when a new technology is introduced for monitoring and none of the multi-parameter monitors are using the new technology yet.

If you use “option 3”, you need to be careful that the ability of your subject device to be used for a second indication does not compromise the performance of the device for the first indication. For example, bone fixation plates are designed for fixation of bone fractures. If the first indication is for long bones, and the second indication is for small bones in the wrist, the size and strength of the bone fixation plate may not be adequate for long bones or the device may be too large for the wrist.

If you would like to learn more about demonstrating substantial equivalence, please join us for a live webinar during Thursday’s Learning Lunch. To register for the webinar, please visit the following webpage.

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510k Submission Section 4: Indications for Use Case Study

The example of a spinal pedicle screw was used for this indications for use case study. This article illustrates the 510k submission requirements for an indications for use statement in section 4 of your 510k submission.

PASS LP Spinal System 510k Submission Section 4: Indications for Use Case Study

A hypothetical new client asked me if I could help them with a 510k submission for a new pedicle screw design. The company’s device utilizes a lower-profile version of a traditional pedicle screw that is pre-packaged with rods, hooks, clamps and nuts. The pre-packaged system is gamma irradiated, and the product is specifically designed for pediatric patients. Unfortunately, the company was only able to find similar designs of pedicle screws that were for adult patients.

Identifying the FDA Regulation

The applicable FDA regulation for a pedicle screw product is 21 CFR 888.3070 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=888.3070) – pedicle screw spinal system. However, the only indication stated as part of this regulation is specific to “skeletally mature patients.” Therefore, the indications portion of the regulation is not applicable to the subject device for my hypothetical client.

Identifying the Product Classification

If you type in “pediatric” as a keyword into the product classification database, there are 12 different product classification codes that result from that search. The applicable product classification code for this product is “OSH” (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?ID=4313)—“Pedicle Screw Spinal System, Adolescent Idiopathic Scoliosis.” The definition for this product classification is: “Intended to stabilize the thoracolumbar spine as an adjunct to fusion using allograft and/or autograft to treat adolescent idiopathic scoliosis.” This is the desired indication, because it is specific to pediatric patients. This product classification code also references “pedicle screw spinal system” as the regulation description and there is a link provided for the 888.3070 regulation number.

Identifying a Predicate Device

There are 97 establishment registration and listing entries under the “OSH” product classification code. Medicrea Technologies (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/rl.cfm?rid=138996), located in France, submitted one of the most recent 510k submissions (K150049) referencing this product code. There are many other possible predicate devices that could be used for this 510k submission, however, a recent 510k submission with the same indications for use is usually a good choice. The description of the potential predicate device in the 510k summary indicates that the predicate is also pre-sterilized, but the predicate device description does not specific that it is a low-profile version. Additional research on the company’s website revealed that the PASS LP Spinal System is a low-profile polyaxial spine system. For a 510k submission, it is more important to select a predicate that has the same indications—rather than a predicate that has all the same technological characteristics. This particular predicate device, however, appears to have most of the same technological characteristics as well. The minor differences between the “Pass LP Spinal System” and the subject device are insignificant and the K150049 was selected as a predicate device submission.

A History of Indications for Use Statements

The US FDA released a guidance document on February 6, 1996. The guidance document is specific to the topic of Indications for Use statements. Here is the link for that guidance document:

http://www.fda.gov/RegulatoryInformation/Guidances/ucm080275.htm

This guidance requests that 510k premarket notification submitters provide the indications for use on a single page. The FDA provides a standard form for documenting in the indications for use (FDA Form 3881):

http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm360431.pdf

FDA Form 3881

The form has four sections to complete:

  1. The 510k number assigned by the FDA to each premarket notification submission – this may be unknown if not assigned yet.
  2. The device name for the subject of your 510k submission.
  3. The indications for use, which should match the indications for use of the predicate device and it should be similar to the indications for use as written in the regulations for the product classification.
  4. The type of device—prescription only and/or over-the-counter use.

The form is completed using Adobe Acrobat and saved as a PDF file in order to submit the page as part of your electronic 510k submission. The document is included in section 4 of the 510k submission, but the FDA includes this page as part of the 510k Summary that is published on the FDA website for all 510k cleared devices. For this case study, the 510k number is unknown. The name of the subject device is the “Miniflex Pedicle Screw Spinal System.” The indications for use is: “The Miniflex Pedicle Screw Spinal System is used for posterior non-cervical pedicle screw fixation in pediatric patients. The spinal implants are indicated as an adjunct to fusion to treat adolescent idiopathic scoliosis. The spinal implants are intended to be used with allograft and/or autograft. Pediatric pedicle screw fixation is limited to a posterior approach.” The device type is for “Prescription Use” only.

Writing Your Indications for Use

When you are writing an Indications for Use statement, the easiest approach is to substitute the name of your subject device for the name of the predicate device. Ideally you have chosen a predicate device that matches your subject device in both the indications for use and the technical characteristics. However, it is possible to have a subject device with a narrower indication. For example, the predicate device may be indicated for both adult and pediatric patients, while your subject device may be specifically designed to better fit pediatric patients. For our case study, only the last paragraph of the predicate’s IFU was applicable to the subject device, because the device was limited to pediatric use. Therefore, the last paragraph was copied and the subject device name was substituted for the predicate device name.

Broader Indications for Use

The first step of the 510k review process is verification that the subject device has the same indications for use as the primary predicate device. Therefore, if broader indications for use are claimed for the subject device then the 510k submission is likely to be rejected as not substantially equivalent (NSE). In this case you have a few options. One alternative for submissions that require a broader indication for use is to perform a clinical study in order to provide safety and efficacy for the broader indication. A second alternative is to submit a De Novo application. The following FDA webpage provide guidance on the topic of De Novo applications:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm232269.htm

It is recommended that you request a pre-submission meeting with the FDA before pursuing either option. In the case of a clinical study, you should plan to provide the FDA with a clinical study synopsis that includes a benefit/risk analysis. The clinical study synopsis should also include a rationale for why the broader indication for use presents a non-significant risk if you plan to conduct the clinical study under good clinical practices (GCPs) instead of submitting an application for an investigational device exemption (IDE). If you plan to submit a De Novo application, then it is recommended that you prepare a special controls guidance document in advance of the pre-submission meeting in order to obtain feedback from the FDA. For novel devices of medium risk, it is quite possible that your company may need to conduct a clinical study and submit a De Novo application.

Your Next 510k Submission

Most companies have plans for subsequent submissions to expand the functionality of the subject device. In this case, often the subject device is the best choice of a predicate device for subsequent 510k submissions. In this case, you should attempt to make the initial application as broad as possible with regard to indications for use. This will enable you to narrow the indications for use in future submissions without the device being NSE to your own predicate device.

If you are interested in watching a webinar on the topic of indications for use, please visit the following webpage:

http://robertpackard.wpengine.com/510k-submission-section-4-indications-for-use-webinar/

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

Performance Testing for a 510k Submission-Case Study-Part 2 explains the performance testing for a 510k submission in order to obtain clearance from the US FDA for marketing a new medical device. Performance testing is the most important part of new product development, and is usually the last section that you are able to 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 very large. In fact, 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 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 in order 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 included 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 are applicable to your screw, and create an overall verification and validation plan.

It is important 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 begin preparation of your 510k submission. Performance testing often takes several months to complete. If you begin 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 is not allowed by the FDA for a 510k submission. Your subject device must be “equivalent” or “not worse than” the predicate device with regard to 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

Posted in: 510(k)

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