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EU MDR delay – a huge miss

The industry is cheering for the EU MDR delay, but the historic amendment represents a huge missed opportunity to amend the EU IVDR.EU Regulation 1 year delay 1 EU MDR delay   a huge missOn Friday, April 17, 2020, the European Parliament voted 693 votes in favor, one against, and two abstentions for the EU MDR delay. Parliament voted in favor of a one year delay for the date of entry into force of the EU MDR from May 26, 2020, to May 26, 2021. Although device companies were confident that European regulators would delay the implementation of the EU MDR, regulators repeatedly insisted that it was critical to renew the public confidence in the European device regulations. Implementation of the EU MDR would not be delayed. Then the COVID19 pandemic happened, and the EU Council and Parliament cooperated in the creation of a historic amendment to delay the implementation date.

What else was changed in this amendment?

The Commission originally proposed the delay of implementation due to the public health emergency caused by the COVID19 virus. The Council moved forward with the proposal as a first reading, and Parliament adopted the first reading with only two minor corrections. The amendment also includes an essential amendment to Article 59, “Derogation from the conformity assessment procedures.” The amendment allows the Commission to issue Implementing Acts that extend emergency measures from a single member state to the whole EU. This effectively creates an additional emergency market access mechanism under the three current directives before the EU MDR comes in to force. This could prove to be important in the current health crisis created by the coronavirus.

Manufacturers are still not out of trouble

Notified Bodies (NBs) were not anticipating a delay in the EU MDR implementation date. Therefore, NBs that had not applied for designation were expecting to no longer need to support the MDD and the AIMD after May 26, 2020. Personnel have left those NBs in many cases, and the resources to support the MDD and AIMD for another year may not be available.

NBs were refusing to quote new CE Certifications under the MDD and AIMD, because there was not enough time to complete new certifications before May 26, 2020. However, with the EU MDR delay, there is an additional year in which to process other applications for CE Certification. The question is whether NBs will have the resources to process additional applications under the current directives.

The transition deadlines for the use of inventory have not been delayed, and therefore manufacturers now have one year less of a transition from the directives to the EU MDR. Any certificates issued under the MDD and AIMD will still become invalid on May 26, 2024, because this amendment did not extend the latest date of validity for certificates issued under current directives. The NB bottleneck has also not disappeared. Any NBs that have not successfully been designated under the EU MDR by the end of this year will not be a position to significantly help alleviate the bottleneck before the delayed date of enforcement.

Why wasn’t the EU IVDR delayed along with the EU MDR delay?

Implementation of the EU IVDR is arguably in a more difficult position that the EU MDR, because there are not enough NBs that applied for designation under the EU IVDR, and the IVD industry must shift from approximately 20% requiring NB involvement to 80% requiring NB involvement by May 26, 2022. This is expected to result in a shortage of CE Marked IVD products in the EU, and the bottleneck industry has experienced for medical devices will be more severe for the IVD manufacturers. The Commission could still initiate a proposal to delay the implementation of the EU IVDR. Even, it would seem logical to take this opportunity to delay the date of both regulations coming into force at one time when there was almost unanimous support for the amendment.

The Commission’s original proposal stated, “As the coronavirus crisis increases demands for certain vital medical devices, it is crucial to avoid any further difficulties or risks of potential shortages or delays in the availability of such devices caused by capacity limitations of authorities or conformity assessment bodies related to the implementation of the Medical Devices Regulation.” This argument for delaying the EU MDR would seem to be equally valid for the EU IVDR. Also, the amendment made to Article 59 could be made to the equivalent section of the EU IVDR (i.e., Article 54). In the current crisis, the power of the Commission to expand the availability of in vitro diagnostic tests is critical. Therefore, limiting the amendment to the EU MDR seems like a huge missed opportunity.

What the EU IVDR needs that was not possible for the EU MDR delay

The EU MDR was less than 60 days from the date of enforcement when the Commission presented its proposal for the amendment to delay the EU MDR. Therefore, it was necessary to forgo formal procedures for review and approval of amendments. We have more than 750 days until the date of enforcement for the EU IVDR. Therefore, there is more time for the Commission to think carefully about any additional changes that might be desired in the fight against a global pandemic. The need for rapid market access for in vitro diagnostic tests, both molecular and serological tests, will be crucial in the coming months for identifying people with active infections and resistance to the virus. Hopefully, the Commission will watch, learn, and take preventive action in the form of an amendment to the EU IVDR.

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Implant Card Requirement – A New Requirement of EU 2017/745

This article breaks down and reviews the new implant card requirement as well as Article 18 of EU 2017/745.

We also have available for sale, SYS-037 Implant Card Procedure written to be Article 18 compliant of Regulation (EU) 2017/745, and includes;

  • SYS-037 A, Implant Card Procedure
  • FRM-044 Checklist for Information to be supplied to the patient with an implant
  • FRM-045 Implant Card Checklist for Article 18 Reg 2017-745
  • Native Slide Deck for Implant Card Webinar
  • Recording of the Implant Card Webinar

Implant Card Procedure Implant Card Requirement   A New Requirement of EU 2017/745

Implant Card Requirement, a new requirement from Regulation (EU) 2017/745.

One of the new changes to the regulation is an introduction of a new requirement for implantable devices. These devices must now come with an “implant card” that contains information about the implanted medical device for the patient. The responsibility of the implementation of the new implant card rules lies with the manufacturer of the implantable device and the health institution as required by the EU member states.

What is an implantable device?

Before discussing the specifics of the implant card, we must first define what an implantable device is to determine if the implant card requirements apply to your device or devices. Article 2 Definitions, number 5 of Regulation (EU) 2017/745 defines and outlines what is considered an implantable device.

(5) ‘implantable device’ means any device, including those that are partially or wholly absorbed, which is intended:

– to be introduced in the human body, or

– to replace an epithelial surface or the surface of the eye,

By clinical intervention and which is intended to remain in place after the procedure.

Any device intended to be partially introduced into the human body by clinical intervention and intended to remain in place after the procedure for at least 30 days shall also be deemed to be an implantable device;

(Taken from http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745 English version)

Is my device considered implantable?

Working with the above definition of an implantable device, you can now compare those requirements against your own devices to determine if they are considered to be an implantable device or not. This can be done by performing a gap analysis of the definition against your device.

Consider what your device is and ask yourself the following questions:

Is my device intended to be partially or wholly absorbed?

If the answer is no, then your device may not be an implantable one. If it is, then you must keep asking yourself questions until you can sufficiently determine your device’s status as implantable or not.

Is my device intended to be introduced in the human body?

No. Ok, that is fine, but is it intended to replace an epithelial surface or the surface of the eye?

To make an awful analogy of the process, it is almost like playing a game of Guess Who with your device. Instead of asking your device if they have red hair or a mustache, you have to ask your device questions like, “Are you intended to remain in place after the procedure?”.

The gap analysis is fine, but you also have to consider some other factors within the wording of the definition. Be careful navigating the specifics because the devil is in the details. In the definition, which is only eighty-nine words long, by the way, uses the word “intended” three different times.

That is important because the definition applies not only to some of the characteristics and uses of the device but also to the intent behind the device. Just because the device can be wholly introduced into the body does not mean that the device is ‘intended’ to be. A better example would be, by clinical intervention, can your device remain in place after the procedure? Could it, perhaps, but is it intended to be? Also, is it the intent of the device to be done so by clinical intervention?

Where to find the implant card requirement?

Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices is where the introduction of implant cards can be found. The definition of an implantable device is found in Article 2 Definitions, definition number 5.

Article 18- ‘Implant card and information to be supplied to the patient with an implanted device’ is where the implant card requirements can be found. This article contains three sections and four subsections pertaining to implant cards.

Article 18 Implant card requirement and information to be supplied to the patient with an implanted device

Below is article 18 in its entirety so that we can discuss it further in detail.

“1. The manufacturer of an implantable device shall provide together with the device the following:

(a) information allowing the identification of the device, including the device name, serial number, lot number, the UDI, the device model, as well as the name, address and the website of the manufacturer;

 

(b) any warnings, precautions or measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions;

 

(c) any information about the expected lifetime of the device and any necessary follow-up;

 

(d) any other information to ensure the safe use of the device by the patient, including the information in point (u) of Section 23.4 of Annex I.

The information referred to in the first subparagraph shall be provided, to make it available to the particular patient who has been implanted with the device, by any means that allow rapid access to that information and shall be stated in the language(s) determined by the concerned Member State. The information shall be written in a way that is readily understood by a layperson and shall be updated where appropriate. Updates of the information shall be made available to the patient via the website mentioned in point (a) of the first subparagraph.

Also, the manufacturer shall provide the information referred to in point (a) of the first subparagraph on an implant card delivered with the device.

  1. The Member States shall require health institutions to make the information referred to in paragraph 1 available, by any means that allow rapid access to that information, to any patients who have been implanted with the device, together with the implant card, which shall bear their identity.
  2. The following implants shall be exempted from the obligations laid down in this Article: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips, and connectors. The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend this list by adding other types of implants to it or by removing implants therefrom.”

(taken from http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745)

Who does the implant card requirement apply to?

Section 1. of Article 18 states explicitly that it is the manufacturer who shall supply the information. Fortunately, it is also outlined what information needs to be included and some guidance on how to provide the information.

Take note, though, that the article states it “shall” be provided, “together with the device.” This means that merely having the information available or accessible such as a downloaded PDF on your website, is not sufficient to comply with section 1. Because that is not being supplied together with the device as outlined.

Section 2. of Article 18 applies to member states’ requirements of health care institutions.

Section 1 of Article 18

Section 1 is by far the most extended section of the article and outlines precisely what information must be provided with the implantable device. Not only is this information that must be provided, it specifically must be provided by the manufacturer. The subsections are broken down by topic and can be summarized as the information, warning, maintenance, and misc. Sections.

Section 1. Sub-Section A

This sub-section outlines the specific identifying information that must be provided. It is even specifically “information allowing the identification of the device.” For devices that are produced and manufactured compliant with other standards such as ISO 13485 or the QSR portion of the United States Code of Federal Regulations, a lot of this information is the same information that is required for traceability.

Besides the generic “information allowing the identification of the device,” the other specific information that ‘shall’ be provided is:

  • The name of the device,
  • The device serial number,
  • The lot number of the device,
  • The UDI,
  • The model of the device,
  • The name of the manufacturer,
  • The manufacturers address,
  • The manufacturers’ website.

They don’t just want your device’s driver’s license; they want the driver’s license, library card, passport, blood type, and favorite color. This is done for a purpose but also carries some implications on the maintenance actions of the manufacturer.

First such strict ID requirements mean that the device is traceable and identifiable. There should be absolutely no doubt about who made the device. In the event of an incident, that device should be traceable back to when and where the individual components were created and assembled into the final device. For traceability of an incident, tracking for corrective or preventive action, or just general inventory tracking this is the type of strict diligence that is expected when the end-user or patient is receiving medical care with an implantable device. There is no demonizing of this requirement. Yes, it is strict, but it is also just part of good housekeeping for a manufacturer in general. Only now it must be provided to the patient receiving care with the device as well.

What is implied is that the information provided along with the device is somewhat of a living document, and the information could vary a bit from patient to patient. Because things like lot numbers or any number of trackable metrics used with the UDI are included, the implant card information cannot be generically the same for each device but that it will have sections that are specific to individual devices. Sure this may initially create some logistical headaches for keeping track that the implant cards don’t get mixed up in situations where the devices are being manufactured, but this creates a level of accountability that is designed for the ultimate safety of the end patient.

Section 1. Sub-section B

Sub-section B contains the warning information of the device. The first part is pretty self-explanatory as meaning literally what is stated “any warnings” and “precautions”. It is the next part that I do not interpret literally. Where it says “measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions”.

If I were the manufacture of an implantable medical device, I would most definitely include measures to be taken by the patient as well as measures to be taken by a healthcare professional. There are a couple of spots that use the word ‘or’, and if it were me, I would read it ‘as well as’.

I say that for a few reasons. One is that without explicit clarification of a governing body as exactly what a silly little word like that is intended to me, this creates an area that is open for debate. Does that ‘or’ mean that at least one of those needs to be included and the rest can be excluded?

As one who likes to err on the side of caution, if you have the information available, why would you not provide it? By going above and beyond not only demonstrates your goodwill but also avoids hang-ups where an auditor might not agree with how you viewed the requirement, and you end up with a nonconformity, or in the same situation with an incident investigator. Ink is cheap; liabilities are expensive.

Section 1. Sub-section C, and Sub-section D.

These two subsections are relatively short and straight forward.

“(c)         any information about the expected lifetime of the device and any necessary follow-up;

How long can the user expect your device to last once it has been implanted?  I there any maintenance they should be performed? Perhaps once a year, a physician needs to double-check the device placement?

(d)         any other information to ensure the safe use of the device by the patient, including the information in point (u) of Section 23.4 of Annex I.”

The rest of Section 1. Of Article 18.

“The information referred to in the first subparagraph shall be provided, to make it available to the particular patient who has been implanted with the device, by any means that allow rapid access to that information and shall be stated in the language(s) determined by the concerned Member State. The information shall be written in a way that is readily understood by a layperson and shall be updated where appropriate. Updates of the information shall be made available to the patient via the website mentioned in point (a) of the first subparagraph.

Also, the manufacturer shall provide the information referred to in point (a) of the first subparagraph on an implant card delivered with the device.”

(Taken from http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745 English version)

At the end of this section, it provides a little bit more information about the purpose of the article but also lays out some guidelines for how to make the required information available.

I specifically mentioned earlier that having the information slapped on a website is not enough by itself. The text states, “any means that allow rapid access to that information”. Certainly, available on the internet is a means that allows rapid access, and it is if you have internet. Using a web-based approach like that is assuming that all the possible patients all have the technology and budget to reach the information. This means that every single possible patient needs a means to access the internet, and the money to pay for internet access. Also, being able to simply access the information rapidly isn’t necessarily providing the information “together with the device” as required.

You also need to have a conversation with your notified body and determine what languages are required by the member state in which your device is sold. It does not do the patient much good if they do not understand the language in which the information is being presented. It also needs to be presented in easy to understand terms, not in technical jargon.

Updates, unlike the initial presentation of information, needs to be included on your website. Specifically, the website that was included in the implant card given to the patient.

Section 2. of Article 18

Unlike what we saw in Section 1. Section 2. Outlines requirements for the health institutions and not the manufacturer. More specifically, Section 2. Requires member states to require health institutions to perform actions.

This section makes health institutions provide the same information that manufacturers had to provide to patients who have been implanted with a device, with the same stipulations as to how the information is provided. However, it also includes the health institution to include their identity on the implant card as well.

  1. Member States shall require health institutions to make the information referred to in paragraph 1 available, by any means that allow rapid access to that information, to any patients who have been implanted with the device, together with the implant card, which shall bear their identity.

(Taken from http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745 English version)

Exemptions allowed in Article 18.

Section 3 of Article 18 is the list of exempted implants, exempted devices are:

  • Sutures
  • Staples
  • Dental Fillings
  • Dental Braces
  • Tooth Crowns
  • Screws
  • Wedges
  • Plates
  • Wires
  • Pins
  • Clips

This is not an exhaustive list and can change with time at the discretion of the Commission. What it has done is taken implanted devices and exempted some of the most common and widely used ones. Thankfully so too, imagine if every staple needed an implant card to be presented to the receiving patient with individual batch and identifying numbers. Then coordinate the effort with a health institution so that the card also bears their identification as well. This would quickly become exhaustive.

  1. The following implants shall be exempted from the obligations laid down in this Article: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips, and connectors. The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend this list by adding other types of implants to it or by removing implants therefrom.”

(Taken from http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32017R0745 English version)

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Auditing Technical Files

This article explains what to look at and what to look for when you are auditing technical files to the new Regulation (EU) 2017/745 for medical devices.

Auditing Technical Files what to look at and what to look for 1024x681 Auditing Technical Files

Next week, August 8th @ Noon EDT, you will have the opportunity to watch a live webinar teaching you what to look at and what to look for when you are auditing technical files. Technical files are are the technical documentation required for CE Marking of medical devices. Most quality system auditors are trained on how to audit to ISO 13485:2016 (or an earlier version of that standard), but very few quality system auditors have the training necessary to audit technical files.

Why you are not qualified for auditing technical files

If you are a lead auditor, you are probably a quality manager or quality engineer. You have experience performing verification testing and validation testing, but you have not prepared a complete technical file yourself. You certainly can’t describe yourself as a regulatory expert. You are a quality system expert. A couple of webinars on the new European regulations is not enough to feel confident about exactly what the content and format of a technical file for CE marking should be.

Creating an auditing checklist

Most auditors attempt to prepare for auditing the new EU medical device regulations by creating a checklist. The auditor copies each section of the regulation into the left column of a table. Then the auditor plans to fill in the right-hand columns of the table (i.e., the audit checklist), with the records they looked at and what they looked for in the records. Unfortunately, if you never created an Essential Requirements Checklist (ERC) before, you can only write in your audit notes that the checklist was completed and what the revision date is. How would you know if the ERC was correctly completed?

In addition to the ERC, now called the Essential Performance and Safety Requirements (i.e., Annex I of new EU regulations), you also need to audit all the Technical Documentation requirements (i.e., Annex II), all the Technical Documentation on Post-Market Surveillance (i.e., Annex III), and the Declaration of Conformity (i.e., Annex IV). These four annexes are 19 pages long. If you try to copy-and-paste each section into an audit checklist, you will have a 25-page checklist with more than 400 things to check. The end result will be a bunch of checkboxes marked “Yes,” and your audit will add no value.

Audits are just samples

Every auditor is trained that audits are just samples. You can’t review 100% of the records during an audit. You can only sample the records as a “spot check.” The average technical file is more than 1,000 pages long, and most medical device manufacturers have multiple technical files. A small company might have four technical files. A medium-sized company might have 20 technical files, and a large device company might have over 100 files. (…and you thought the 177-page regulation was long.)

Instead of checking a lot of boxes, “Yes,” you should be looking for specific things in the records you audit. You also need a plan for what records to audit. Your plan should focus on the most important records and any problem areas that were identified during previous audits. You should always start with a list of the previous problem areas because there should be corrective actions that were implemented, and the effectiveness of corrective actions needs to be verified.

Which records are most valuable when auditing technical files?

I recommend selecting 5-7 records to sample. My choices would be: 1) the ERC checklist, 2) the Declaration of Conformity, 3) labeling, 4) the risk management file, 5) the clinical evaluation report, and 6) post-market surveillance reports, and 7) design verification and validation testing for the most recent design changes. You could argue that my choices are arbitrary, but an auditor can always ask the person they are planning to audit if these records would be the records that the company is most concerned about. If the person has other suggestions, you can change which records your sample. However, you should try not to sample the same records every year. Try mixing it up each year by dropping the records that looked great the previous year, and adding a few new records to your list this year.

What to look for when auditing technical files

The first thing to look for when you audit records: has the record been updated as required? Some records have a required frequency for updating, while other records only need to be updated when there is a change. If the record is more than three years old, it is probably out of date. For clinical evaluation reports and post-market surveillance reports, the new EU regulations require updating these reports annually for implantable devices. For lower-risk devices, these reports should be updated every other year or once every three years at a minimum.

Design verification and design validation report typically only require revisions when a design change is made, but a device seldom goes three years without a single change–especially devices containing software. However, any EO sterilized product requires re-validation of the EO sterilization process at least once every two years. You also need to consider any process changes, supplier changes, labeling changes, and changes to any applicable harmonized standards.

Finally, if there have been any complaints or adverse events, then the risk management file probably required updates to reflect new information related to the risk analysis.

Which record should you audit first?

The ERC, or Essential Performance and Safety Requirements checklist, is the record you should audit first. First, you should verify that the checklist is organized for the most current regulations. If the general requirements end with section 6a, then the checklist has not been updated from the MDD to the new regulations–which contains nine sections in the general requirements. Second, you should make sure that the harmonized standards listed are the most current versions of standards. Third, you should make sure that the most current verification and validation reports are listed–rather than an obsolete report.

How to learn more…

If you want to learn more about how to audit technical files, please register for our webinar on auditing technical files–August 8th @ Noon EDT. We also provide a new audit report template specifically written for your next technical file audit.

Posted in: Auditing, Technical Files

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MDR Quality Plan – for EU Regulation 2017/745 Compliance

This article outlines an EU MDR quality plan for compliance with European Regulation 2017/745 for medical devices by the May 26, 2020 transition deadline.

Days until MDR Transition 1024x126 MDR Quality Plan   for EU Regulation 2017/745 Compliance

Biggest MDR quality plan mistakes

Implementing an MDR quality plan is not just about updating your technical file and the procedures specific to CE Marking of medical devices. You need to make sure that you have planned to provide adequate resources for the successful implementation of your plan. Resources fall into four major categories, and all four should be addressed in a formal MDR quality plan that you have reviewed and approved during a management review meeting (i.e., ISO 13485:2016, Clause 5.6.3d). First, you need to provide adequate training. Second, you need to provide adequate equipment–such as UDI printing software and an electronic quality system database. Third, you need to provide adequate personnel. Fourth, you need to revise and update your quality system procedures.

European companies concentrated enormous resources in 2018 to prepare for the implementation of the EU Regulations in 2020. This may seem early, but most of those companies are realizing they should have started in 2017–immediately after Regulation 2017/745 was approved by the European Parliament and Council. In contrast, most companies in the USA were focusing on ISO 13485:2016 certification and MDSAP certification. Unfortunately, many CEOs were told that there is a “soft-transition,” and they have until 2024 to implement the new regulations. While it is true that most CE Certificates issued by notified bodies will be valid until their expiration date, and that date could be as late as May 25, 2024, it is not true that companies have until 2024 implement the new regulations. Quality system requirements in Article 10 of the MDR, and compliance with the MDR for economic operators, must be implemented by May 26, 2020. Any medical devices that are being reclassified will require full implementation by May 26, 2020, as well. Finally, notified bodies cannot renew 100% of the CE Certificates on May 25, 2020, to give manufacturers the full 4-year transition for certificates. Your certificate will expire based upon the certificate renewal cycle that is already established.

Required procedures for your EU MDR quality plan

You might not know that ISO 13485:2016 certification is not required for CE Marking of medical devices. Although ISO 13485 certification is the most popular way for companies to demonstrate quality system compliance with EU regulations, the actual requirement is to comply with the thirteen procedural requirements in Article 10 of EU Regulation 2017/745. Specifically, those thirteen procedures are:

  1. Conformity assessment procedure / significant change procedure – SYS-025
  2. Identification of safety and performance requirements (i.e., Essential Requirements Checklist) – FRM-038
  3. Management responsibilities – SYS-003
  4. Resource management, including suppliers – SYS-004 and SYS-011
  5. Risk management – SYS-010
  6. Clinical evaluation – SYS-041
  7. Product realization, including design, production, and service – SYS-008, SYS-012, and SYS-013
  8. UDI requirements – SYS-039
  9. Post-market surveillance – SYS-019
  10. Communication with competent authorities notified bodies and other economic operators – SYS-049 (new requirement)
  11. Vigilance reporting, including serious incidents and field safety corrective actions – SYS-036 and SYS-020
  12. Corrective and preventive actions – SYS-024
  13. Monitoring and measurement of processes – SYS-017

Note: If you are interested in one of the procedures listed above that does not have a hyperlink, please contact me via email at rob@13485cert.com. The procedures are available, and the links will be provided during the next two weeks. The only exception is SYS-026. That is a new procedure in draft format, and it will be the subject of a future blog. Medical Device Academy will be revising each of the above procedures for compliance with EU Regulation 2017/745 in accordance with the MDR quality plan that we have outlined in this blog article. These procedures are all compliant with ISO 13485:2016, and updates for compliance with the EU MDR will be made available at no additional charge.

The priority of requirements for MDR quality plan

There are seven major changes required for compliance with the European Regulation 2017/745. These priorities are listed in order of highest to lowest effort and cost that will be required to comply, rather than the chronological order. First, some medical devices are being reclassified. Second, new CE certificates must be issued under the new conformity assessment processes. Third, technical documentation must be updated to meet Annex II of Regulation 2017/745. Fourth, post-market surveillance documentation must be updated to comply with Annex III of Regulation 2017/745. Fifth, specific documentation must be uploaded to the Eudamed. Specifically, manufacturers must upload UDI data, labeling, and periodic safety update reports (PSUR). Sixth, all economic operators must be registered with Eudamed and comply with Regulation 2017/745, or new economic operators will need to be selected. Seventh, quality system procedures will need to be updated to comply with Regulation 2017/745.

The implementation timeline for MDR quality plan

If any of your devices are being reclassified, you will need to implement all of the above changes before the May 26, 2020 transition date. For example, reusable medical instruments are currently Class I medical devices, and manufacturers utilize Annex VII of the MDD as the conformity assessment process. Under EU Regulation 2017/745, these reusable instruments will require notified body involvement to issue a CE Certificate. This is a lot of work to complete in 17 months (i.e., 513 days and counting), and notified bodies will have a large backlog of technical files to review for existing customers before they can review documentation for new customers.

If your company already has CE Certificates for your medical devices, and none of your devices are being reclassified, you will need to implement only the sixth and seventh items listed above before the May 26, 2020 deadline. Uploading information to Eudamed is likely to be extended beyond the May 26, 2020 deadline, and the transition may be staggered by risk classification–just as the US FDA did for UDI implementation in the USA. The second, third, and fourth changes listed above will require compliance before your existing CE Certificate(s) expire. The best-case scenario could be four (4) years after the transition deadline.

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MEDDEV 2.7/1 rev 4: How will your clinical evaluation change?

Article overviews of the new MEDDEV 2.7/1 rev 4 for clinical evaluation of medical devices, including a quality plan to comply with the latest revision.

MEDDEV 271 rev 4 MEDDEV 2.7/1 rev 4: How will your clinical evaluation change?

What’s new in MEDDEV 2.7/1 rev 4 for clinical evaluations?

The third and fourth revisions both give manufacturers three choices: 1) a clinical literature review, 2) performing a clinical study, and 3) a combination of literature review and performing a clinical study. However, the fourth revision is completely re-written. The fourth edition is 19 pages longer, and it is now much harder to use the “literature only” route. The fourth revision includes stringent requirements for demonstrating equivalence between another device and your device. Therefore, many companies are now struggling to update their clinical evaluation reports to satisfy this new guidance document.

Overview of the content in MEDDEV 2.7/1 rev 4

The third and fourth revisions of the guidance both have a 5-stage process for clinical evaluations, but in the third revision, only articulated stages 1 through 3 as stages leading up to writing a clinical evaluation report. The figure in section 6.3 of revision four now identifies a planning Stage 0, and the writing of the clinical evaluation report is referred to as Stage 4. Therefore, there is a lot more detail describing the planning and report writing stages than there was in revision 3. In addition, Stage 2 (Appraisal of clinical data) has been expanded from a single page to eight pages.

Based upon the above changes, you can infer that Competent Authorities have been unsatisfied with the quality of clinical data being provided to support the essential requirements for safety and performance. In turn, Notified Bodies are expected to be much more critical of the data presented, and more guidance is provided to manufacturers. There is also much more guidance and more examples provided in the appendices, while the 12-page clinical evaluation checklist that was provided in revision three has been replaced by one page of bulleted items for Notified Bodies to consider.

Demonstration of equivalence

It is no longer sufficient to list several devices that are similar to your device and include those devices in your search of clinical literature. Now you may only select one device for equivalence. You must also provide a thorough analysis of equivalence with that device based on clinical, technical, and biological characteristics. This comparison includes providing drawings or pictures to compare the size, shape, and elements of contact with the body.

Updating clinical evaluations

The new European Medical Device Regulations (EMDR) is expected to specify minimum requirements regarding the frequency of updating clinical evaluations, but MEDDEV 2.7/1 rev 4 discusses this in section 6.2.3. The frequency of updating your clinical evaluations must be justified and documented. Many considerations for this justification are discussed, but the end of that section indicates that devices with significant risks (e.g., implants) require at least annual updates to the clinical evaluation report. For devices with non-significant risks, and where the device is well established (e.g., a long clinical history), 2-5 years is the range of possible frequency. Longer than five years are not allowed.

Who should perform clinical evaluations?

Many device manufacturers are receiving nonconformities because the evaluators are not sufficiently qualified, or the qualifications are not documented. The qualifications must follow 6.4 of the new guidance, and the qualifications set by your company should be documented in your procedure for clinical evaluations. You will need to document these qualifications with more than an abstract, but you will also need to present a declaration of interest for each evaluator. Evaluators need knowledge in clinical study design, biostatistics, information management, regulatory requirements, and medical writing. Evaluators also need knowledge specific to the device, its technology, and its application. Evaluators must also have a higher education degree in the field and five years of experience or ten years of experience if they do not have a higher education degree. Due to the breadth and depth required of qualifications required, it may be necessary to assemble a team to perform evaluations.

Creating a quality plan for compliance with MEDDEV 2.7/1 rev 4

Seven steps need to be included in your quality plan for compliance with MEDDEV 2.7/1 rev 4:

  1. update your external standards to replace MEDDEV 2.7/1 rev 3 with MEDDEV 2.7/1 rev 4
  2. revise your procedure and associated templates for a literature review and clinical evaluation report to meet the requirements of MEDDEV 2.7/1 rev 4
  3. document the qualifications of evaluators for clinical evaluations
  4. document a plan/schedule for updating your clinical evaluation reports for each product family
  5. train evaluators, regulatory personnel and any applicable internal auditors on the requirements of MEDDEV 2.7/1 rev four and updated procedures and forms
  6. begin updating clinical evaluations according to your plan
  7. perform an internal audit of your clinical evaluation process

Learning more about MEDDEV 2.7/1 rev 4

If you are interested in learning more about this revised guidance document, please register for our live webinar on Friday, January 27 @ Noon EST by clicking on the button below.

Click Here 300x115 MEDDEV 2.7/1 rev 4: How will your clinical evaluation change?

Posted in: CE Marking, Clinical Studies & Post-Market Surveillance

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Finally, New European Medical Device Regulations are Confirmed!

This article announces confirmation of the New European Medical Device Regulations by negotiators of the Dutch presidency of the Council and EU Parliament.

Confirmed Finally, New European Medical Device Regulations are Confirmed!

Announcement of New European Medical Device Regulations

Yesterday, May 25, the European Parliament and the Dutch presidency of the Council reached an agreement and it was announced in press release.

The agreement is subject to confirmation by permanent members of the Council and Parliament’s Envi Committee. The new regulations include the following substantial changes:

  • A scrutiny process for high risk (i.e., Class IIb implants and Class III) products
  • Eudamed database will be expanded to provide public access to information about Notified Bodies, Economic Operators (i.e. – manufacturers, importers, distributors, authorized representatives, etc.) and comprehensive product information
  • Eudamed database will become publicly accessible for searching market surveillance and vigilance data (similar to the FDA’s MAUDE database)
  • Implementation of a Unique Device Identifier (UDI) requirement in Europe.

The Eudamed database will be an invaluable global resource for manufacturers, physician and patients.

Next Steps for New European Medical Device Regulations

The next step in the process of approving the new regulations is an invitation of the Council’s Permanent Representatives Committee and the Parliament’s ENVI Committee to endorse the agreement. The regulations will finally be adopted by the Council and the Parliament after Committee approvals and we can expect implementation of the regulations this fall. The new regulations will have a three year transition after publication for medical devices and a five year  transition for in vitro diagnostic medical devices.

MedTech Summit June 13-17

On June 13 I will be in Brussels at the MedTech Summit hosted by Informa Life Science. There will be 300+ attendees with a fantastic assembly of industry experts representing the Competent Authorities, Notified Bodies and manufacturers. This meeting provides a unique opportunity to learn and discuss the details of the New European Medical Device Regulations and the challenges we will all face in the preparation for the transition to the New European Medical Device Regulations. I will have the pleasure of speaking about risk management and its integration with device design, post-market surveillance and labeling. I will also be Chairperson for the Labeling Stream in June 16.

Please stay tuned to my blog feed. I will be posting related blogs over the next month.

Register for the MedTech Summit

Click on the blue text above to register or you can also call Informa Life Sciences at: +44 (0) 20 7017 7481 or registrations@informa-ls.com.

New Live Webinar on MDRs June 9, 2016

I’m releasing an updated procedure for MDRs and I am offering webinar bundle to train people how to comply with 21 CFR 803 and the procedure. The webinar is scheduled for June 9. I’m even offering two times to accommodate companies in Europe as well as the USA.

Here’s a link for the webinars page.

Posted in: CE Marking

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

This article summarizes the three (3) crucial technical files 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

Three 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, 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 an 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 a 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 issues 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 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 that 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 the clinical studies may not cover changes to the device, accessories, and range of sizes. MEDDEV 2.12/2 provides guidance on the requirements for post-market clinical follow-up (PMCF) studies. Still, most companies manufacturing moderate-risk devices do not have experience obtaining patient consent to access medical records 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.

Posted in: 510(k), CE Marking

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Regulatory pathway document creation–a case study

Medical Device Academy provides this regulatory pathway case study for 510k Submission, CE Marking application and Canadian Medical Device License application.

Regulatory Pathway 1 Regulatory pathway document creation  a case study

How do you select the right regulatory pathway for your device?

Manufacturers considering global expansion need to master the process of creating a regulatory pathway analysis. That analysis must be product-specific. I used to create long documents that were tedious to read, but in the past month, I found a better way. I now use webinar recordings to help clients analyze the regulatory pathway for their products. I create slides for each market that my client is considering for expansion. At the end of the 20-30 minute presentation, my client asks clarification questions, and we discuss the possible next steps toward regulatory approval.

A Typical Regulatory Pathway Analysis

A typical regulatory pathway analysis involves three major markets for a new product: 1) USA, 2) Europe, and 3) Canada. There will be one slide per market identifying the classification rationale for each market, and if there are exceptions, this will be explained. Exceptions often arise for specific indications for use, duration of contact, and unique components such as:

nanomaterials (Class III in European new regulations)
– antibiotics (Class III as per Rule 13 or combination product)

Recommended Regulatory Pathway Document Content

There will be a slide per market identifying the regulatory approval process. For devices without predicates, this will be a De Novo application or a PMA submission in the USA. For Canada, you might need an Establishment License or a Medical Device Distribution License.

There will be a slide per market, identifying QMS requirements customized to reflect the QMS my client already has. If you already have ISO 13485 certification, you only need 2-3 new procedures to launch in Canada. At the same time, there are typically more procedures required for launching a product in the USA due to differences between ISO 13485 and 21 CFR 820. Even in Europe, a Japanese company will need: 1) a vigilance reporting procedure, changes to their Advisory Notice Procedure and 3) a procedure for creating a technical file.

Finally, most clients need help in identifying the testing requirements for safety and efficacy. If the FDA has recent special controls guidance, this is much easier. If guidance is non-existent or outdated, then you need experts like Leo to help navigate international and European National (EN) Standards that might be applicable for safety and efficacy testing.

Regulatory pathway case study

In 2015 I published a series of three blogs explaining how to identify the regulatory pathway for different markets:

  1. CE Marking Approval of a Medical Device (Case Study)
  2. 510k Submission to the FDA (Case Study – Part 1)
  3. Obtaining a Health Canada Medical Device License (Case Study)

The blogs were specific to a hypothetical product–a tissue adhesive for topical approximation of skin. Therefore, I decided to use the same hypothetical product for this case study regulatory pathway. If you are interested in watching a recording of this regulatory pathway, click here to download the case study recording.

Are you planning submission in 2016?

Please visit our regulatory pathway webpage if you are interested in purchasing this service.

Posted in: CE Marking

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Avoiding Clinical Evaluation Report (CER) Pitfalls

This article explains the key steps to preparing a successful clinical evaluation report (CER) for the submission of a technical file for medical device CE Marking.

Photo for Clinical Evaluation Report Blog 1024x931 Avoiding Clinical Evaluation Report (CER) Pitfalls

Once someone shows you the most efficient path, climbing the wall no longer seems so challenging.

Essential requirement 6a, the clinical evaluation report (CER), is required for all medical devices that are CE Marked. Up until the Medical Device Directive (MDD) was modified in 2010 (i.e., 2007/47/EC), only high-risk devices required a clinical evaluation report. After the MDD was changed, a CER was needed for all medical devices–even Class I devices that do not require a Notified Body. To help manufacturers understand the expectations and comply with this requirement, a guidance document was released for clinical evaluations in December of 2009 (i..e., MEDDEV 2.7/1 rev 3). MEDDEV 2.7/1 indicates that are there are three options for preparing a clinical evaluation report:

  1. perform a clinical study and summarize the results,
  2. perform a literature search of clinical study articles, or
  3. a combination of the first two options.

Preparing clinical evaluations are tedious but not necessarily challenging. I like to compare the preparation of clinical evaluation reports to bouldering problems. Once someone shows you the most efficient path, climbing the wall no longer seems so challenging.

Literature Search Protocol (TMP-004)

Section 6.1 of the guidance document indicates that a literature search protocol should be used to identify, select, and collate clinical study articles for a literature search. Critical elements of your search protocol should include: which search databases you selected and why, intended use and indications for the use of the device, similar devices that are on the market and a comprehensive date range starting with the earliest clinical studies or the last date of a previous clinical evaluation. Your search protocol should specify inclusion and exclusion criteria, and you will need a systematic method for tracking your results.

I created a protocol template, TMP-004, which I use to perform clinical literature searches. The protocol includes suggested databases for literature sources, a list of adverse event databases, and a database for clinical investigations that should be included in your search. The protocol also includes criteria for evaluating the results of the search. Evaluation criteria should consist of the type of clinical study, the number of patients, the study design, etc.

Qualified Individuals

To conduct a clinical evaluation, you need a cross-functional team–as you should have for all post-market surveillance and risk management activities. One of the team members should be an expert in the design of the device or similar devices. Another person should be an expert in performing literature searches to ensure that the review of the literature is comprehensive. Finally, the team needs at least one person with a clinical research perspective to evaluate the clinical data critically. The qualifications of these individuals should be described in an appendix of your clinical evaluation report, and typically this is done by providing a copy of each person’s resume or curriculum vitae. The omission of these qualifications or the failure to rely upon clinical experts to review the data is a common nonconformity raised by technical reviewers from Notified Bodies.

Selection of Databases

When you are writing a literature search protocol, it is essential to specify why you selected certain search databases and to ensure that you include more than one database. Each literature search database has different strengths and weaknesses. Suppose you are not sure which databases to choose and why this is an indication that you need assistance with the literature search methodology. This is typically part of the process for teaching doctoral candidates how to prepare for writing their dissertation. Therefore academic credentials of the individuals contributing to the post-market surveillance activities are relevant.

Selection of Key Words

Often certain keywords are more common in the title of clinical study articles than others, and these keywords can help narrow the number of literature search results dramatically. Therefore, it is recommended to perform some preliminary searches with different keywords to get a sense of which terms will be the most efficient in helping you to identify the articles that meet your inclusion criteria. These terms can also be used to exclude large numbers of articles that are not relevant. For example, if there are a large number of porcine studies in the literature, you might exclude the term “porcine” to ensure that animal studies involving pigs are excluded from your search results.

Inclusion & Exclusion Criteria

Many times articles will mention a keyword or the name of a device, but the device is only mentioned as an accessory in a study rather than being the focus of the study. If the article only says the device but doesn’t include clinical data regarding its use, then the article should be excluded. Only human studies should be included in your results, and if there are a large number of published studies, you may purposely choose to exclude articles with the terms “case study” that may only include one or two patients.

Addressing Risks

Your clinical evaluation report (CER) is intended to assess the safety of your device by identifying any potential risks that you may have overlooked in your risk analysis and to help you estimate the severity of harm and the probability of occurrence for those harms. It is recommended to perform a preliminary hazard identification and risk analysis before conducting the clinical evaluation to identify the most likely risks associated with the device. Each of these risks should be mentioned explicitly in the clinical evaluation–even if the clinical study data does not identify the risk. If a specific risk is identified during your hazard identification with no clinical data to support the safety of the device related to that risk, then it may be necessary to conduct a clinical study or a post-market clinical follow-up (PMCF) study to evaluate the risk further.

Review of Post-Market Surveillance

When your device is first submitted for CE Marking, you may not have any clinical history with the device, and it is only possible to estimate risks. For this reason, it is important to include post-market surveillance information about similar products as an input to your clinical evaluation process. After your product is launched, you will have a complaint handling data and adverse event data specific to your device. Therefore, you should periodically review the post-market surveillance data and compare it with the initial risk estimates. If the results are similar, then the risk analysis does not need to be updated immediately. If the post-market surveillance results are substantially different from your risk estimates, you should update your clinical evaluation report earlier than planned and update your risk analysis. I recommend stating this conclusion in each report summarizing post-market surveillance data–including a specific recommendation to maintain the current plan for the frequency of conducting clinical evaluations or a recommendation to change the schedule.

Appraisal of Clinical Literature

Your appraisal of clinical literature needs to be systematic and documented. Technical reviewers expect clinical data that supports and detracts from the conclusion that your device is safe and effective for the desired indications. Therefore, you should not exclude articles simply because the findings are negative. You need to include appraisal criteria in your protocol to ensure that the evaluation of literature search results is objective and systematic. I have included a recommended grading system for clinical study articles in my procedure for clinical evaluation reports (i.e., SYS-041). The graded results of each article identified are then summarized in the Appendices of the clinical evaluation report (CER).

Review and Update of Clinical Evaluation Reports (CERs)

Preparing a clinical evaluation report (CER) is time-consuming, but the report is also a living document. Therefore, you need to have a post-market surveillance plan for each medical device or device family that specifies the frequency of performing a review and update of your clinical evaluation report (CER). Depending upon the nature of your device and the amount of clinical history you have with that device, you may also need to conduct a post-market clinical follow-up study (PMCF). Any post-market surveillance that you conduct should be included as an input to the clinical evaluation report. This is why my literature search protocol includes adverse event databases.

Procedures & Templates

If you are looking for a procedure and literature search protocol for preparing a clinical evaluation report (CER), 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.

Photos shown in this article are two of my sons, Alex Beshay (13) and Bailey Packard (14), at this weekend’s bouldering competition at PETRA Cliffs in Burlington, VT. Every member of our family is an avid rock climber, including my 3-year-old daughter.

Posted in: CE Marking, Clinical Studies & Post-Market Surveillance

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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 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. Their auditor told the other client 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)?
  • Does the master file have 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, there 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 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 an 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 Biocompatibility

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 to reduce the 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 the 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 undoubtedly 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. Issues 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 the 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 did the 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. Still, 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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