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Strategic planning of a mock FDA inspection

This article shows you how to think strategically when you plan a mock FDA inspection to ensure that you successfully prevent an unpleasant FDA inspection.

strategic planning Strategic planning of a mock FDA inspection

For the past couple of years, several clients have asked me to conduct mock FDA inspections to prepare them for a potential FDA inspection. I am writing from Shanghai, China, where I am conducting a mock FDA inspection for a medical device client with another auditor from the company’s business unit in the USA.

The mock FDA inspections I conduct are internal audits and technically not an inspection because inspectors are looking for nonconformities, and I am looking for conformity with the FDA regulations (i.e., 21 CFR 820, 21 CFR 803 and 21 CFR 806). Inspections are conducted by FDA investigators that are conducting an inspection in accordance with the FDA QSIT manual (http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074883.htm). I use the process approach to conduct audits of the four major quality systems that FDA inspectors focus on during an FDA inspection. Still, as an auditor, I have several advantages that an inspector doesn’t.

  1. I can evaluate auditees and coach them on how to respond to an FDA inspector more effectively.
  2. I can teach my client’s internal auditors and management team how to use internal audits and Notified Body audits as practice for their next FDA inspection.
  3. I can avoid any area that my client wants me to and focus on areas of concern.
  4. I can help my client identify the most likely product or product family to be targeted by the FDA.
  5. I can give my client advice and help them implement corrective actions.
  6. I can teach my client how to respond to potential FDA Form 483s to avoid a Warning Letter.

Opening meeting for a mock FDA inspection

FDA inspections are not planned, but it is important to make sure that the right people are available and present during a mock FDA inspection, or your “inspector(s)” may not be able to review the records or interview the most important people. Therefore, I provide an agenda ahead of time, indicating which processes I will be auditing on which days. My agenda for a mock FDA inspection begins with an opening meeting, but the purpose of this opening meeting is primarily training. I take advantage of having all the senior managers in one room as an opportunity to explain how they can benefit most from the audit, and to remind them of what to expect during a real FDA inspection.

CAPA Sources

After the opening meeting, I take a brief tour—unless I already know the facility well. Before I leave for the tour, I ask my client to be prepared for me to begin auditing nonconformities, complaint handling, MDRs, and recalls when I return to the conference room. I select these areas because the FDA always starts with the CAPA process, but they look closely at the sources of CAPAs at the same time. I believe that inspectors rarely take “random samples.” Instead, most inspectors use the sources of CAPAs to help them bias there sampling of CAPAs.

Production and Process Controls

The next major process in my agenda after CAPAs and sources of CAPAs is production and process controls. The sequence of my process for auditing this area is always the same: 1) request the Device Master Record (DMR) for the target product or product family, 2) request two or more recent Device Master Records (DHRs) that were associated with a complaint record or MDR (remember samples are never random), and 3) I then go to the production areas identified in the DHR, and I try to interview the people that produced the lot identified in the DHR—rather than the people the department manager feels are the most experienced. This process of working backward from complaint records and MDRs to the activities on the production floor often allows me to help companies identify a root cause that they missed when the complaint or MDR was initially investigated.

Design Controls

Auditing a Design History File (DHF) is about as exciting as watching paint dry for most auditors. Still, I am always fascinated with how things work, so I am more engaging with the design team members I interview during a mock FDA inspection. I also like to focus on aspects of the design that have proven to be less than perfect—by reviewing nonconformities, complaints, MDRs, recalls, and CAPAs first. For example, if I see several complaints related to primary packaging failures, I am going to spend more time reviewing the shipping validation and shelf-life testing, than I might normally allocate.

Management Processes

The FDA is somewhat limited in this area because, in accordance with 21 CFR 820.180(e), the records of internal audits, supplier evaluations, and management reviews are exempt from FDA inspections. During a mock FDA inspection, I do not have this constraint. Therefore, I will often look more closely at these three areas than an FDA inspector to make sure my client has effective management processes. While procedures and schedules are the focus of an FDA inspector, I will make sure that the problems I observed in nonconformities, complaints, MDRs, and recalls are being addressed by management. As a quality manager, this is not always easy to do. Still, as an independent consultant, I have the luxury of being blunt when a senior manager needs to hear from someone other than the typical “yes men.” I also can use this part of mock FDA inspections to benchmark best practices I have learned from the hundreds of companies against what my client is currently doing to manage their quality system.

When to schedule a mock FDA inspection

Scheduling a mock FDA inspection immediately after an FDA inspection is pointless, but there is an optimal time for scheduling your mock FDA inspection. The FDA target is to conduct inspections once every two years for Class II device manufacturers. However, some district offices do better or worse than this target. Therefore, it’s important to keep track of the typical frequency in your district and the date of your last inspection. If the FDA is on a two-year cycle, you want to conduct your mock FDA inspection approximately 6-9 months before the next FDA inspection to ensure that you have time to implement corrective actions before the FDA inspector arrives.

Additional Resources

If you are interested in learning more about this topic, I highly recommend watching and listening to my free webinar on how to prepare for an FDA inspection:

http://robertpackard.wpengine.com/how-to-prepare-for-an-fda-medical-device-inspection/

In addition to preparing for an actual inspection, every company must know how to respond effectively to an FDA 483 inspection observation:

http://robertpackard.wpengine.com/7-steps-respond-fda-483-inspection-observation/

In addition to my blog, I also have recorded a webinar on this topic:

http://robertpackard.wpengine.com/7-steps-respond-fda-483-inspection-observation-webinar/

Finally, every manager needs to be reminded that FDA 483s are just another opportunity to write a CAPA and improve their quality system. Therefore, do yourself a favor and watch my new webinar on creating a risk-based CAPA process:

http://robertpackard.wpengine.com/create-a-risk-based-capa-process/.

Posted in: FDA

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21 CFR 820.180 – Exceptions to the US FDA’s Record Requirements

21 CFR 820.180 Exceptions to the US FDA’s Record Requirements 21 CFR 820.180   Exceptions to the US FDA’s Record RequirementsThis article provides practical advice for how to deal with records the FDA is not allowed to request during an inspection and FDA inspector tactics specific to 21 CFR 820.180 – exceptions. When I meet with a new consulting client, the phrase I dread hearing is “the FDA can’t see that.” Indeed, the FDA is not supposed to review the content of internal audit reports, supplier audit reports, and management reviews to encourage companies to use these tools to address quality problems without having to worry about the FDA beating them with their reports. This policy is officially stated in subsection C of 21 CFR 820.180–exceptions:

21 CFR 820.180 – Exceptions

“[21 CFR 820.180 – exceptions] does not apply to the reports required by 820.20(c) Management review, 820.22 Quality audits, and supplier audit reports used to meet the requirements of 820.50(a) Evaluation of suppliers, contractors, and consultants, but does apply to procedures established under these provisions. Upon request of a designated employee of FDA, an employee in management with executive responsibility shall certify in writing that the management reviews and quality audits required under this part, and supplier audits where applicable, have been performed and documented, the dates on which they were performed and that any required corrective action has been undertaken.”

The Problem with Hiding Records

The problem with the mentality of hiding things from the FDA is that it fails every time. The FDA can get to issues in your management reviews and your internal audits by asking, “Can I please see all the CAPAs resulting from audits and management reviews.” One client I spoke with said that they purposely don’t open any CAPAs from audits or management reviews for that reason. I was in complete shock, but I managed to keep my poker face and asked the client, “So what do you think the FDA will do when you say that you don’t have any CAPAs resulting from audits or management reviews?” Management responsibility is a frequent FDA inspection target. Most companies are subjected to a Level 2, QSIT inspection on a biannual basis. During these comprehensive inspections, the inspector reviews the four major subsystems: 1) management controls, 2) design controls, 3) CAPA, and 4) production and process controls. The FDA will ask open-ended questions to determine the effectiveness of the QMS. If the inspector is not going to look at the actual meeting minutes from the management review, you can expect them to look at the following apparent targets:

  1. “May I see your procedure for Management Reviews?”
  2. “May I please have a copy of your organization chart?”
  3. “Could I see the agenda and attendees list from your last management review?”

The inspector could also ask for copies of inputs that are identified in the Management Review procedure, such as: “Could I have a copy of the most recent scrap trend analysis for production?” or “What is your threshold for taking corrective actions for rejects found in receiving inspection?” One Quality Manager told me a fascinating story about his local inspector. During a previous inspection, the inspector requested a copy of the management review. The Quality Manager showed him the cover page that indicated the agenda and the attendees. The Quality Manager refused to let the inspector see the rest of the meeting minutes. The inspector then proceeded to conduct a brutal 3-day inspection where a myriad of 483’s was written. Twelve months later, the inspector returned to perform a “Compliance Follow-up.” This time when the inspector asked to see the management review, the Quality Manager agreed to let the inspector see the entire meeting minutes. From that point onward, each time the inspector got close to identifying a new 483’s, the inspector would stop following the audit trail at the last moment before the nonconformity was identified. The Quality Manager said it was almost like the inspector was showing him that he could find all kinds of problems to write-up if he wanted to. Still, he was taking it easy on the company because the Quality Manager was cooperative. My philosophy is to create a QMS that is open for review by any customer, auditor, and even the FDA. No matter what they find, it’s just another opportunity to improve. This has worked well for me, but you need to follow a few basic rules when writing audit reports and management review meeting minutes.

Rules for Writing Audit Reports & Management Reviews

  1. DO NOT write anything inflammatory or opinionated in your documents. My motto is, “Stick to the facts, Jack (or Jill).”
  2. I ask other people in the management team to read and review the meeting minutes before they are finalized. The variety of perspectives in top management helps to make sure that the final document is well written and clear—especially to FDA inspectors.
  3. I structure the documents as per a standard template that is a controlled document. This ensures that each report or management review was conducted as per the procedure. I typically reference the applicable clauses and sub-clauses throughout the document. For example, I will reference ISO 13485:2003, Section 5.6.2h) for the slide titled “New and Revised Regulatory Requirements.” I put the reference next to the slide title just to make it clear what requirement this slide is addressing.
  4. If there is an area that I covered, but there was nothing to discuss, I write, “There was no further discussion on this topic.”
  5. If there is an area that I did not cover, I make sure I do the following:
  6. write a justification for not covering the area,
  7. indicate the last time the area was covered (and the result at that time), and
  8. document when the area will be covered in the future.

You can continue to listen to the advice of consultants that think of creative ways to hide things from the FDA, or you can follow the above advice. If you follow my advice, then you can spend the rest of your time working on the CAPAs for each area where you identified a weakness—instead of spending your time trying to hide your problems. If you need help preparing for an FDA inspection or responding to FDA 483 inspection observations or warning letters, please email Rob Packard. We have two people on our team that used to work for the agency.

Posted in: FDA

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Selecting and Changing the European Authorized Representative

This article explains the roles and responsibilities of a European Authorized Representative for CE Marking of medical devices. The article also provides advice on selecting and changing the European Authorized Representative.

How to Select or Change Your European Authorized Representative Selecting and Changing the European Authorized Representative

European Authorized Representatives are the legal representative of non-European manufacturers for medical devices sold in Europe. If a company already has offices located in Europe, an Authorized Representative is not needed. However, if you don’t have offices in Europe, you must have a legal agreement with an Authorized Representative that is physically located in Europe to be your primary contact for receipt of customer complaints. The Authorized Representative can also act as your liaison between the Competent Authority in Europe and your company.

Why your distributor is not the right choice

Many manufacturers located outside of Europe choose their distributor as an Authorized Representative. Distributors often want to do this, because then their name is required to appear by law on the labeling and the IFU. Unfortunately, your distributor has a conflict of interest. The distributor does not want adverse event reporting, recalls, or even complaints. Therefore, can you be sure that the distributor will notify you immediately of all potential complaints?

In January 2012, the European Commission released a guidance document explaining the roles and responsibilities of European Authorized Representatives: MEDDEV 2.5/10. Distributors rarely have the regulatory expertise to act as an Authorized Representative.

Competent Authorities occasionally audit Authorized Representatives to ensure that the legal requirements are being met. When this happens, clients often ask me to recommend a European Authorized Representative to switch to.

Primary Responsibilities

The EU Authorized Representative has two primary responsibilities:

  1. Complaint handling
  2. Registration of CE Marked devices

The complaint handling function is the reason why the name and address of the European Authorized Representative must appear on the product labeling and IFU. Your distributor may still become aware of potential complaints, and therefore, distributors should still be trained on the importance of forwarding any potential complaints to your company immediately. The registration function is critical for Class I devices that are non-sterile and do not have a measuring function, because those devices do not have a Notified Body involved. It is often valuable to have an Authorized Representative located in one of the Member States where you intend to sell a larger percentage of the product because the labeling will include a physical address in that Member State.

Other ways an Authorized Representative Can Help

Some manufacturers complain that they are paying $3,000-$5,000 each year for a competent authority to do very little. However, Authorized Representatives are required to review your procedures before CE Marking, and anytime you notify them of an update. This additional review of procedures is equivalent to hiring a consultant to review your procedures.

European Authorized Representatives can be helpful at other times too. For example, if your company and your Notified Body do not agree on the classification of a device, the Authorized Representative may be able to assist you in the same way that an experienced regulatory consultant can. If you receive communication from a Competent Authority, the Authorized Representative can act as your liaison. Most important of all, the Authorized Representative can help you determine when complaints require vigilance reporting and provide support if a recall or advisory notice must be initiated.

How to Select an Authorized Representative

I recommend a three-step approach to selecting your Authorized Representative. First, visit the EAARMED website. One of the 15 members of this association should be your starting point because these are the most experienced Authorized Representatives. Next, you should determine which of the 15 members is located in a country that matches the country you intend to sell in. For example, if 100% of your sales are through a distributor located in Italy, Donawa would be a better choice than a German Authorized Representative. Finally, you should obtain quotes and interview more than one Authorized Representative. You want to make sure that the Authorized Representative is responsive and easy to communicate with. It’s surprising how much we learn about responsiveness and communication during the quoting process.

If you need any additional help preparing for the CE Marking product in Europe, please email Rob Packard.

Posted in: 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 if you cannot identify a 510(k) predicate device

  1. Conduct a Clinical Study and Prepare a PMA Submission = $$$ + 2 years min.
  2. Prepare a De Novo Submission = avg. review time was 307 days in 2019
  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 the front of Project
  5. Submit a 513(g) Request to the FDA = $ + 60-day Delay at Front of Project

Option 1 – Clinical Study & PMA preparation

If you cannot identify a predicate device, you may need to conduct a clinical study to demonstrate that your new device is safe and efficient. 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, likely, 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.

Option 2 – De Novo Classification Request if there is no predicate device

Originally the De Novo process was created with IVD products in mind where the technological characteristics are nearly identical between the two devices. Still, the intended use is different (i.e., the 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. We recorded a webinar on the De Novo Classification Request Process in 2019. The FDA also recently updated the De Novo webpage to summarize the regulations related to the De Novo new final rule. The following FDA webpage summarizes all the De Novo Classification Requests recently granted.

Option 3 – Submit a 510k with whatever device you found

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 receive 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-sub meeting to discuss a potential predicate device

If you are not able to identify a suitable predicate, you might consider preparing a classification rationale and selecting 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 webinar on pre-submission meeting requests.

The webinar includes specific dos and don’ts for pre-submission meetings. There is also final guidance for the pre-submission program that was released last year on February 18, 2014. The FDA pre-submission guidance document was updated again on January 6, 2021, and we recorded a webinar on pre-submission meeting requests.

Option 5 – Submit a 513(g) application to identify the regulatory pathway

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, the 513(g) process may not be your best choice for two reasons. First, the 513(g) process takes 60 days before the FDA responds. 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 about 510(k) predicates?

Rob Packard recorded an updated webinar on the topic of predicate selection. If you are interested in this topic, please register for the webinar. The updated webinar was recorded on March 28, 2022.

Posted in: 510(k)

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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 quickly 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 a way that the material 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 boiler plating, and other sections do not apply 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 nine sections should be written and reviewed by someone 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 the 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 are 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.

Posted in: 510(k)

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Status of the European Medical Device Regulations?

This article describes the status of the new European Medical Device Regulations, and it provides some advice for what you should be doing to prepare for the changes.

MudI 600x334 Status of the European Medical Device Regulations?

The picture above is not a picture of people on their way to the local maple sugar shack, trying to get a car unstuck during mud season in Vermont. It’s actually a photo of paid actors reenacting the European negotiations for new medical device regulation. The European Parliament is in the overcoat on the left. The four men on the right represent the various presidents–Greek, Italian, Latvian, and Luxembourg. The Dutch President is driving the horse team in the front in the hopes of getting unstuck in time for next Spring.

Yes, in a word, the negotiations are “stuck”!

My friend Erik Vollebregt did a wonderful job of summarizing the status of negotiations on April 30, in his blog posting. The best guess anyone has is that we might have a final version released next year in Spring 2016. It’s only two years later than I was expecting. I guess they encountered more mud than expected.

There are a number of issues that the member states appear to be stuck on:

  • Ingested products
  • Non-medical devices
  • Companion diagnostics
  • Non-viable human tissues and cells
  • Viable biologic substances
  • Reprocessing single-use devices
  • Genetic testing
  • Implant cards
  • Eudamed & UDI
  • Summary of safety & performance
  • Notified Bodies
  • Pre-market approval
  • Clinical investigations
  • Post-market surveillance
  • Market surveillance & vigilance
  • Reference laboratories
  • Hazardous chemicals
  • Classification rules
  • Governance & oversight

I’m not quite sure whether the remaining list of issues the member states agree upon is shorter than this or longer. Still, this list includes a number of fundamental principles that could dramatically change the nature of medical device regulation in Europe. We expect that many of these issues will be resolved with a compromise of some sort. Still, I suspect every medical device manufacturer with a CE Mark will be extremely busy from 2016-2019 revising their procedures, technical documentation, and training personnel on the new European Medical Device Regulations.

 What Should You Be Doing to Prepare?

  1. Update Your Quality System to ISO 13485:2015 Early – The second Draft International Standard (DIS2) for ISO 13485 was released in February, and the final version is expected to be published this Fall. The changes to ISO 13485 are minor, but audits by your Notified Body will be far less complicated if you upgrade your quality system to the new revision before you attempt to address the new European Medical Device Regulations.
  2. Strengthen Your Internal Auditing & CAPA Processes – Companies with strong internal audit programs and CAPA processes have fewer findings resulting from Notified Bodies. When you have multiple outcomes from a previous audit to close, your annual surveillance audits and recertification audits become longer and more complex. These findings must also be closed before a manufacturer may transfer a quality system or CE Certificate from one Notified Body to another. Therefore, strengthening your internal audit and CAPA processes will result in a shorter Notified Body audit, and you will find it much easier to transfer from one Notified Body to another–if your current Notified Body is no longer able to issue a CE Certificate for one or more of your products.
  3. Update Your Technical Files – Companies that have a Design Dossier are required to submit all changes to their Design Dossier for approval before implementation. Still, companies with a Technical File for a lower risk device have their technical documentation sampled periodically. A sampling of technical documentation allows companies to fall behind in their documentation of changes. Re-issue of new CE Certificates will require a more thorough review of these Technical Files that may not have been sampled in several years. Therefore, I recommend that companies allocate resources to updating technical documentation now so that there is less work to update the technical documentation for the new European Medical Device Regulations.
  4. Review Your Product Portfolio and Prune It – The more mature product lines become, the more likely it is that you have products you are maintaining that just aren’t selling. The cost of maintaining your technical documentation and updating everything for compliance with the new European Medical Device Regulations will be expensive. Therefore, you can save some money now and a larger amount of money later by eliminating any products from your CE Certificate that is not selling well. If you have customers that are still buying an older version of the product, now is the time to persuade them to transition to the current version of your product. You don’t want to maintain your Technical File for two versions of the same product.

Regardless of what compromises are made, the new European Medical Device Regulations are guaranteed to be the most substantial change in regulatory requirements that the medical device industry has endured since 2003–much more dramatic than the 2007/47/EC amendment to the Medical Device Directive (MDD).  

Will someone please buy the negotiators a pair of Bogs and a Subaru Crosstrek?

Subaru XTrek 300x199 Status of the European Medical Device Regulations?

Bogs Status of the European Medical Device Regulations?

Posted in: CE Marking

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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 a product that affects 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 (an 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 the 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. Any device that a manufacturer intends to sell for more than $250 requires a report issued by an independent public accountant.
  • IRB approval for the 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 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 the 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. 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 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 to receive 510k clearance. 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 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, can 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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CE Marking Approval of a Medical Device (Case Study)

This article explains the process for CE Marking approval of a medical device. For this case study, I selected the same hypothetical client that I chose for my case study on Canadian Medical Device Licensing and a 510k submission to the US FDA. The product is a cyanoacrylate adhesive sold by the makers of Krazy Glue®. This hypothetical client wants to expand its target market to include the healthcare industry by repackaging and marketing the product as a topical adhesive in Europe.

CE marking case study CE Marking Approval of a Medical Device (Case Study)

My client called to ask if I could help obtain CE Marking approval. In Europe, cyanoacrylate is a medical device when it is used as a topical adhesive. My first step is to determine the device classification as per Annex IX in the Medical Device Directive (93/42/EEC as modified by 2007/47/EC). Instead of relying solely upon the Directive, I use guidance documents published on the Europa website–specifically MEDDEV 2.4/1 rev 9 (the following link explains the European MEDDEV guidance documents – http://bit.ly/Whats-a-MEDDEV).

I identified three potential device classifications: 1) Class 1 as per Rule 4 (a non-invasive device which comes into contact with injured skin, if the device is intended to be used as a mechanical barrier, for compression or absorption of exudates); 2) Class 2a as per Rule 7 (a surgically invasive device intended for short-term use [i.e., < 30 days] are in Class 2a; and 3) Class 2b as per Rule 8 (an implantable device). These three applications match the three possible indications that I identified when I was reviewing classifications for Canadian Medical Device Licensing for this product.

If this device were not required to be “sterile,” then a Class 1 device could use the Annex VII route of conformity (i.e., self-declaration). However, even generic bandages are sold as sterile devices. Therefore, whether the device is a sterile Class 1 device or a Class 2a device, obtaining CE Marking approval will still require a Notified Body’s review and approval. The most common route would be the Annex V route of conformity. If my client were to launch their product as a “glue” for internal use, then the device would require an Annex II.3 Full Quality System Certificate or the combination of an Annex V Certificate and a Type Examination Certificate (i.e., Annex III).

STOP!

The previous paragraph was hard to understand, but the source of this jargon is Article 11 of the Medical Device Directive. This one section is the best practices in European legalese. If you want to make something almost unintelligible, copy Article 11. If you’re going to understand this stuff, a flow chart of the various routes to conformity is as good as it gets (still hard to understand, but fewer words). The following simplified table is what I use in my CE Marking webinar:

Classification Routes for CE Marking CE Marking Approval of a Medical Device (Case Study)

What you need to know…

My client only has one product family, and they are currently selling the product in Canada for external use by healthcare professionals—not as an implant. Therefore, the device is a Class 2a device requiring an Annex V certificate. My client will need to do the following:

  1. Select a Notified Body
  2. Submit a Technical File for review and approval
  3. Select a European Authorized Representative, because my client does not have a physical presence in Europe

Fortunately, my client already obtained an ISO 13485:2003 certificate with CMDCAS from their current registrar as part of the Canadian Licensing process. Therefore, the changes required for the Quality System consist of adding a few work instructions to meet European-specific requirements, such as vigilance reporting, creating a technical file, and performing clinical evaluations. My client also needs to add the European Requirements as an applicable regulatory requirement in the Quality Manual.

The more significant challenge is an assembly of a Technical File for submission. Since the product is already on the market in Canada, all of the technical requirements have been met. The documentation of these requirements now needs to be converted into a format acceptable to a Notified Body. There are three recommended strategies:

  1. Whatever the Notified Body prefers. Some of the Notified Bodies have a checklist of requirements for a Technical File. If such a list exists, the client should organize the Technical File in the same order.
  2. The GHTF STED format (GHTF/SG1/N011:2008). The Global Harmonization Task Force (http://bit.ly/GHTFSTEDGuidance) published this guidance document to standardize the format for submission of regulatory submissions. This is the format required for Class III and IV Canadian medical device license applications. This is also the format specified in the proposed EU Medical Device Regulations that is expected to be released in 2015.
  3. The NB-MED recommended format (NB-MED 2.5.1/rec 5). This document was created by the “Big 5” Notified Bodies. It provides a template in a two-part format for submissions. This was the format I used most often for auditing files and for creating new files. However, the proposed EU Regulations that are anticipated for release in 2015 are closer to the format of the GHTF guidance. Therefore, I no longer recommend this format.

My client chose option 3 for organizing their Technical File because they have full reports for each of the verification and validation tests that were performed, but creating summaries for each report would take longer than assembling a Technical File with copies of each of these full reports.

In all, I estimate that the overall timescale for completing this project is about 60 days–not including review by the Notified Body. Therefore, I suggested that the client obtain a quotation from their registrar for an Annex V Certificate. In addition, I suggested hiring a consultant from Medical Device Academy to help them with the preparation of a Clinical Evaluation. Before 2010, Clinical Evaluations were only required for high-risk devices. As part of the new MDD, clinical evaluations are now needed for all devices. Since the use of and risks associated with cyanoacrylates is well characterized in published literature, my client may use a literature search method for preparing a Clinical Evaluation as per MEDDEV 2.7/1 rev 3.

My client hired an Authorized Representative to handle European registration, receive customer complaints, and to act as a liaison with the Competent Authority in the event of an adverse event. An Authorized Representative Agreement was signed, and the Authorized Representative recommended a few corrections to procedures they reviewed as part of entering the contract with a new client.

The company also hired another clinical consultant from our firm to complete a literature search and write a Clinical Evaluation in four weeks. The complete Technical File was assembled and submitted to the Notified Body electronically with seven weeks of starting the project. The Notified Body’s first round of questions was received within six weeks. The client and I prepared responses to the questions in a week and submitted them to the Notified Body. Fortunately, the responses were thorough, and the Technical File was well-organized from the start. The Notified completed their final review and recommended the product for CE Marking within three more weeks. The Notified Body conducted two-panel reviews to verify the technical, regulatory, and risk aspects of the submission. Finally, the Annex V certificate was received 12 weeks after the initial submission of the Technical File.

If you are interested in additional training or assistance with CE Marking of medical devices, please email Rob Packard (mail to: rob@13485cert.com). We have standardized procedures to meet each of the requirements in the European Regulations and a couple of webinar recordings that explain both the Medical Device Directive and how to create a technical file or design dossier.

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510k Submission Section 4: Indications for Use Case Study

The example of a spinal pedicle screw was used for this indication 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 specially 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 does not apply 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. Many other possible predicate devices 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. Still, the predicate device description does not specify 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 offers 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 the 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 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 are: “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 most straightforward 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 to provide safety and efficacy for the broader indication. A second alternative is to submit a De Novo application. The following FDA webpage provides 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 to obtain feedback from the FDA. For novel devices of medium risk, 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 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 6, 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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