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

4 Comments / 510(k), CE Marking / By Robert Packard

This article explains the three (3) critical technical file and 510k submission differences: 1) risk, 2) CER, and 3) PMCF.

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

There are many differences between a technical file and a 510k submission, including the fact that technical files are audited annually while a 510k submission is reviewed only once. 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:

compliant with ISO 14971:2007 instead of EN ISO 14971:2012
reduction of risks as low as reasonably practicable (ALARP) instead of reducing risks as far as possible (AFAP)
reducing risks by notifying users and patients of residual risks in the IFU
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 a 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.

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

Oct 26 2015

Avoiding Clinical Evaluation Report (CER) Pitfalls

1 Comment / CE Marking, Clinical Studies & Post-Market Surveillance / By Robert Packard

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:

perform a clinical study and summarize the results,
perform a literature search of clinical study articles, or
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.

Avoiding Clinical Evaluation Report (CER) Pitfalls Read More »

Oct 22 2015

Biocompatibility for 510k Submissions vs CE Marking

1 Comment / 510(k), CE Marking / By Robert Packard

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:

Justifications are PERMITTED as it states in EN ISO 10993-1:2009
Competent Authorities noticed that some of the justifications accepted in the past were not sufficient
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:

the strategy and program content for the biological evaluation of the medical device;
the criteria for determining the acceptability of the material for the intended purpose, in line with the risk management plan;
the adequacy of the material characterization;
the rationale for selection and/or waiving of tests;
the interpretation of existing data and results of testing;
the need for any additional data to complete the biological evaluation; and
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:

Are there any additives, contaminants, and residues remaining on the device?
Are there any substances leachable from the device?
Are there any degradation components of the device?
Are there other components, and how might they interact with the final product?
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.

Biocompatibility for 510k Submissions vs CE Marking Read More »

Jun 10 2015

Selecting and Changing the European Authorized Representative

1 Comment / CE Marking / By Robert Packard

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.

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:

Complaint handling
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.

Selecting and Changing the European Authorized Representative Read More »

May 12 2015

Status of the European Medical Device Regulations?

1 Comment / CE Marking / By Robert Packard

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.

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?

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.
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.
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.
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?

Status of the European Medical Device Regulations? Read More »

Apr 13 2015

CE Marking Approval of a Medical Device (Case Study)

4 Comments / CE Marking / By Robert Packard

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.

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:

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:

Select a Notified Body
Submit a Technical File for review and approval
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:

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.
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.
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.

CE Marking Approval of a Medical Device (Case Study) Read More »

Jul 8 2014

Notified Body Unannounced Audits Have Begun

3 Comments / CE Marking / By Robert Packard / Notified Body, notified body unannounced audit, notified body unannounced audits have begun

This article provides an update on the status of unannounced audits by Notified Bodies for CE Marking of medical devices.

The EU Commission provided recommendations to Notified Bodies last Fall on how they should conduct three different kinds of audits: 1) product assessments, 2) quality system assessments, and 3) unannounced audits (http://bit.ly/Audit-Recommendations). The recommendations do not propose any changes to existing practices for product assessments (i.e., review of CE Marking applications) that are being conducted in accordance with the European Directives, or quality system assessments that are being conducted in accordance with ISO 17021 (http://bit.ly/ISO-17021-2006). The recommendation does, however, propose new auditing practices specific to conducting unannounced audits (http://bit.ly/Unannounced-Audits).

The recommendation is addressed to the Member States, rather than Notified Bodies because the intent is for Competent Authorities in each member state to enforce these recommendations when they are reevaluating existing Notified Bodies for renewal. The intent is that the EU Commission and the Member States will use compliance with the “recommendation” for unannounced audits as one of the criteria for deciding which Notified Bodies would retain their status when the new European Medical Device Regulations were approved in 2015. Therefore, all of the Notified Bodies are scrambling to complete a number of unannounced audits before the end of 2014.

Who will be audited in 2014?

In 2014, the primary targets for unannounced audits will be manufacturers of high-risk, Class III devices. The prime targets for unannounced audits are unlikely to contract manufacturers, because Notified Bodies may not have access to all the technical documentation while they are auditing a contract manufacturer. I expect each of the Notified Bodies to plan at least one unannounced audit of a contract manufacturer for a Class III device that is outsourced. Still, I don’t expect this to be the focus of unannounced auditing activities in 2014.

It is already July, and only a handful of unannounced audits have been performed as “pilots.” Most of the Notified Bodies trained auditors on how to conduct unannounced audits in May or June during their annual auditor training. Therefore, we can expect a dramatic increase in the number of unannounced audits during the remaining months of 2014. If your firm has recently had CE Marking compliance issues with a Class III device, you should expect an auditor soon.

4 Ways unannounced audits are different

Unannounced audits differ from traditional quality system audits in four ways.

1. Unannounced audits are truly unannounced–with no warning at all. Even the US FDA inspectors have the courtesy to call on Friday to inform manufacturers of their intent to visit the following Monday or Tuesday. To ensure that auditors can conduct unannounced audits as planned, Notified Bodies are asking manufacturers to provide information about when production activities will be shut-down.

2. Unannounced audits will always be conducted by an auditing team with at least one person that is qualified to review the technical documentation (i.e., Technical File or Design Dossier) and compare it to the actual production activities. This is similar in some ways to how FDA inspectors review a Device Master Record (DMR) and then compare the DMR to production and process controls they observe in manufacturing. However, the technical experts from Notified Bodies typically have a minimum of five years experience similar designing devices, and a two-person team can spread your resources dangerously thin if you are a smaller company that is used to providing a guide for only one auditor or inspector.

3. Unannounced audits will involve more time spent by auditors in production areas, instead of reading documents in conference rooms. You can expect brief opening meetings because auditors need to review critical processes as quickly as possible. Specifically, the auditors are required to use a risk-based approach to select two of the following processes:

design controls
establishment of material specifications
purchasing control and incoming inspection
assembling
sterilization
batch-release
packaging
product quality control

If a company conducts sterilization on-site, I would expect this to be a likely prospect for sampling. However, the two areas I hope to be sampled most frequently are: 1) purchasing control & incoming inspection, and 2) batch-release. These two processes are expected to be sampled frequently because these processes facilitate ad hoc sampling and demonstration of testing. This is important because Notified Bodies are expected to observe product testing.

4. Unannounced audits will be conducted at suppliers when critical processes are outsourced. Therefore, if Class III device manufacturers outsource final inspection, packaging, and sterilization–the suppliers providing these services may be unannounced audit targets for multiple Notified Bodies. ISO 13485 certified suppliers have enjoyed a decade of little direct involvement by regulators, but unannounced audits are about to change this.

How will unannounced audits change in the future?

In 2015 and beyond, unannounced audits will be conducted at contract manufacturers and manufacturers. Unannounced audits will also be conducted for all risk classifications of devices–unless the device does not have Notified Body involvement (i.e., Class I, non-sterile, and non-measuring devices). The number of unannounced audits will also increase, because Notified Bodies are required to conduct an unannounced audit for each client at least once during three years–and more frequently for high-risk, Class III devices.

What should be done to prepare?

Preparation for unannounced audits should be very similar to your preparation for FDA inspections (http://bit.ly/FDA-Inspection-Webinar). Still, you will now need to evaluate your suppliers more rigorously to ensure they are also prepared for unannounced audits. The FDA rarely visits suppliers, and they are not allowed to review supplier auditing records. Notified Bodies will not have these restrictions. You will need to demonstrate a good balance between incoming inspection activities and other types of supplier controls. If your incoming inspection activities consist primarily of reviewing paperwork, then you need to balance this with supplier auditing (http://bit.ly/Supplier-Audits) and monitoring of in-process and final inspection nonconformities caused by supplier quality problems.

If you are interested in learning more about unannounced audits by Notified Bodies, please click on this link to pre-register for our webinar recording on the topic: http://bit.ly/unannounced-audits-webinar. Pre-registration pricing is $79, compared to our normal webinar price of $129. The pre-registration period ends on July 18.

Notified Body Unannounced Audits Have Begun Read More »

Jun 30 2014

How Are EU Device Regulations Changing and When?

1 Comment / CE Marking / By Robert Packard / EU device regulations, EU device regulations changing, EU Medical Device Regulations, EU medical device regulations changing

This blog, “How Are EU Device Regulations Changing and When?” includes 9 of the most significant proposed changes and compliance deadlines.

The CE Marking process for medical devices is currently defined in three directives:

Medical Device Directive (MDD), 93/42/EEC (http://bit.ly/M5MDD)
Active Implantable Medical Devices (AIMD) Directive, 90/385/EEC (http://bit.ly/AIMDDirective)
In Vitro Diagnostics Directive (IVDD), 98/79/EC (http://bit.ly/currentIVDD)

The EU Commission proposed revising the system from three directives requiring transposition by member states to two regulations: 1) http://bit.ly/EUIVDProposal, and 2) http://bit.ly/EURegs. The most significant proposed changes are:

The Commission will have the opportunity to review recommendations for CE Marking before approval (i.e., the Scrutiny Process)
The ability to create Common Technical Specifications will be expanded from IVDs to all devices
A new class of “Special” Notified Bodies will be created
Notified Bodies will be audited jointly by Competent Authorities
Unannounced audits will be enforced
Spinal implants, devices that control and monitor active implants, nanomaterials, apheresis machines, and combination products will be reclassified as Class III devices requiring a Design Dossier
Most IVD products will require Notified Body involvement
A Unique Device Identifier (UDI) system will be required for labeling, and the Eudamed database will be expanded
Formatting of Declarations and Technical Files will be revised

When Will, the Final EMDR, be Approved?

The EU Commission took from February 2012 to September 2012 to write a proposal for new European device regulations. Parliament took 13 months (i.e., September 2012 to October 2013) to revise and fast-track its version of the new European device regulations, and the Council will probably take a year to finish their version of the regulations. Therefore, the real negotiations between Parliament and the Council will begin after the 2014 summer holiday. The final approval date is unknown, but my current guess is October 2015.

On September 12, 2013, Eucamed released the results of an industry survey (http://bit.ly/CostofEURegs) stating that the proposed regulations are expected to increase the cost of regulatory approvals by 17.5 billion Euros for medical device manufacturers collectively. The details of the survey indicate that implementation of the UDI system improved labeling and clinical performance data will require a 7.5 billion Euro investment to implement new software systems to comply with the UDI regulations. Also, industry survey respondents indicated that an additional 2.5 million Euro investment would be required for each new Class III device that is required to undergo the proposed Scrutiny Process in Article 44. Financial implications and political pressures could force the Council and Parliament to make major revisions to the proposed regulations to reduce the cost of implementation.

Some key elements need to be in place before implementation of the proposed regulations can reasonably begin. First, Notified Bodies need more staff to conduct audits and review technical documentation–especially for high-risk devices. Second, the European Databank of Medical Devices (i.e., Eudamed) must be ready to implement UDI labeling and other documentation required by the EMDR (http://bit.ly/Eudamed). Third, the European Commission plans to build a new centralized organization that will be responsible for oversight of the Notified Bodies. Each of these three elements will take more than a year, and planning has only just begun.

What Is The Compliance Deadline?

The original proposal, released in September 2012, indicated that there would be a three-year transition period for implementation of the EMDR from 2014 to 2017. This transition period would begin with the highest risk Class III devices first, and lower risk devices would be phased in over the three years. However, if the EMDR was finalized in October 2015, the implementation period will end at the end of 2018.

A complete review of the new regulations can be found at http://bit.ly/MDDI-article-EU-Device-Reg-Changes.

How Are EU Device Regulations Changing and When? Read More »

Apr 25 2014

European Medical Device Regulations-4 Key Eucomed Recommendations

1 Comment / CE Marking / By Robert Packard / EMDR, Eucomed, european medical device regulations

“European Medical Device Regulations-4 Key Eucomed Recommendations,” reviews why the Eucomed position paper will help draft the new European Medical Device Regulations.

Eucomed, the medical technology industry representative group for Europe, released a new position paper on April 1, 2014, http://bit.ly/Eucomed-April-2014. This paper was created in response to the proposed European Medical Device Regulations, and focuses on four industry concerns:

1. Introduction of a pre-market “scrutiny process”
2. Revised clinical requirements
3. Restriction of hazardous substances
Re-use of single-use devices

History

The original draft of the proposed regulations (i.e., the proposal) was released by the European Commission on September 26, 2012 (http://bit.ly/EUProposal). Europe’s Parliament Committee for Environment, Public Health and Food Safety (ENVI) voted on the Commission’s proposed regulations on September 25, 2013–after three postponed votes. The ENVI Committee made several revisions to the proposed EMDR (i.e., draft legislation), but in general, the ENVI Committee recommended the proposed EMDR. The European Parliament voted on the proposed regulations on October 22, 2013 (i.e., Plenary Vote). Parliament made additional revisions to the draft legislation and mandated negotiation by Parliament representatives (i.e., rapporteurs) with the European Council.

There were three versions of the new EU regulations for the Council to consider:

A proposal by the EU Commission
Draft legislation by the ENVI Committee
Revised draft legislation by Parliament

Eucomed published a position paper on January 30, 2013 (http://bit.ly/EucomedPositionPaper) in response to the original proposal by the Commission, but Eucomed did not respond to the draft legislation until April 1, 2014. Now, the Council has a fourth version to consider–the 2014 Eucomed position paper.

I expected Eucomed to criticize Parliament’s revised draft before the 2013 holidays, but there was no further public response from Eucomed. Instead of being critical of Parliament’s revised draft, Eucomed focused on four industry concerns and made its recommendations for each issue. The Eucomed position paper is specially addressed to the EU Council with the hope of influencing the Council’s version of the new EMDR.

Pre-market “Scrutiny Process” (Article 44)

The EU Commission introduced the concept of the “Scrutiny Process” in Article 44 of the proposed EMDR. Still, the EU Parliament replaced the “Scrutiny Process” with Article 44a in the Parliament Amendment from the Plenary Vote. Article 44a involved a review by the European Medicines Agency for high-risk submissions. Both of these solutions are unpopular with industry. In the April 2014 position paper, Eucomed does not endorse either version. Instead, Eucomed proposed its process for review of premarket submissions, which is referred to as a “Reinforced Control Procedure.”

The Reinforced Control Procedure is a process that is built into the existing Notified Body process. Eucomed outlined the new procedure in detail as an Annex to the position paper.

Revised Clinical Requirements (Articles 49-60)

Eucomed’s April 2014 position paper endorses the proposed regulations by the EU Commission and does not support the stricter legislation proposed by Parliament that mandates Randomized Control Trials (RCTs). In addition, Eucomed listed the following seven points below that the Council should address to ensure that the new Clinical Requirements are “fit-for-purpose”:

Ensure no “one-size-fits-all” approach
Include appropriate elements from pharmaceutical legislation
Consider that effectiveness is measured across the full lifecycle
RCTs are not always practically possible or ethical
Utilize the power of big data and scientific literature
Consider a balanced concept of equivalence
Importance of intellectual property and know-how for medtech companies

Restriction of Hazardous Substances

Eucomed’s position paper encourages the EU Council to support the European Commission’s proposal on the use of hazardous substances in medical devices–not the Parliament version. Eucomed cites the existing horizontal legislation that is in place (i.e., Reach Legislation, http://bit.ly/REACH-Legislation; and RoHS 2, http://bit.ly/RoHS-2). The position paper points out that Parliament’s proposed ban has the following flaws:

Proposed ban disregards potential benefits offered by these substances
Scope of the proposed ban is broader than can be practically implemented at this time
The three-year implementation period is too short of a timeline
Four-year period for applying for exemptions is too short a timeframe for industry subject matter experts to submit the required requests
The proposed ban is not consistent with the existing REACH and RoHS legislation

Re-use of Single-use Devices

The Eucomed position paper recommends that the EU Council support the EU Commission proposal for addressing the re-use of single-use devices. The Parliament approach stated that all devices should be considered re-usable unless the manufacturer can demonstrate that the device cannot be re-used. The industry response to Parliament’s approach can be summarized in one phrase from the Eucomed paper: “Medical device industry believes that Parliament’s amendments create a potential threat to patient safety.” The Eucomed paper goes on to identify specific deficiencies in the Parliament amendments:

Amendment presents a potential threat to patient safety
The approach is generic and cannot be applied to all products
The process proposed is unclear and may create delays
An amendment is not required by other countries and would increase the cost of products to Europeans
Roles and responsibilities of manufacturers and reprocessors are unclear
Standardization is not feasible

Conclusion

The Eucomed position paper should be helpful to the European Council in framing a more moderate draft for the new European Medical Device Regulations. However, the Council is likely to create a few solutions of its own that will require additional review. I expect to see a draft from the Council this Fall and do not expect Parliament or the Council to reach an agreement on a final version in 2015.

European Medical Device Regulations-4 Key Eucomed Recommendations Read More »

Apr 8 2014

Are MEDDEVs Required or Optional for CE Marking of Medical Devices?

1 Comment / CE Marking / By Robert Packard / CE marking of medical devices, MEDDEV

This blog answers the question of whether compliance with MEDDEV guidance documents is required or optional for CE marking of medical devices.

MEDDEVs are guidance documents (http://bit.ly/Whats-a-MEDDEV) written by competent authorities—not law. As it states on the Europa website (http://bit.ly/MEDDEV), “The guidelines are not legally binding.” However, the Competent Authorities (http://bit.ly/ContactPoints) take an active role in developing these guidance documents. Therefore, enforcement of the guidance documents by Notified Bodies depends upon which competent authorities helped to develop the specific MEDDEV. MHRA. For example, is the competent authority for the United Kingdom (UK). MHRA has taken an active role in developing many of the MEDDEVs. Therefore any manufacturer that uses a Notified Body in the UK is more likely to consider the MEDDEVs that MHRA helped create to be “required” rather than “recommended”. The following Notified Bodies are under the jurisdiction of MHRA, but each member states’ competent authority has Notified Bodies that could be affected, including:

British Standards Institute (BSI) – NB # 0086
Lloyd’s Register Quality Assurance (LRQA) – NB # 0088
SGS United Kingdom Limited (SGS) – NB # 0120
AMTAC Certification Services – NB # 0473
UL International (UK) LTD – NB # 0843

There are 32 MEDDEVs divided into 15 categories. The most recent revision to a MEDDEV was in January 2013 when MEDDEV 2.12/1, Medical Device Vigilance System, was updated. This particular MEDDEV is the European equivalent to 21 CFR 803 for Medical Device Reporting, but reporting of adverse events is called “vigilance” in the EU. It is essential to keep current with changes to MEDDEVs (http://bit.ly/New-Revised-EU-Regulations) because Competent Authorities require vigilance reporting using the most current version of the MEDDEV form. In the case of the vigilance MEDDEV, the guidance is de facto law. However, the French Competent Authority recently indicated that trend reporting requirements will be required in the future for high-risk devices, and the French Competent Authority refused to accept the form associated with MEDDEV 2.12/1. Instead, France has its form that is preferred for vigilance submissions.

MEDDEV Enforcement

Other MEDDEVs are not as consistently enforced. For example, MEDDEV 2.5/10 (http://bit.ly/ECREPMEDDEV) provides guidance with regard to the roles and responsibilities of European Authorized Representatives. In some cases, Competent Authorities audit Authorized Representatives for compliance with this MEDDEV. Notified Bodies are also auditing agreements between manufacturers and Authorized Representatives. Unfortunately, many manufacturers still rely upon European distributors that are not compliant with MEDDEV 2.5/10, and Notified Body auditors are merely verifying that an Authorized Representative agreement exists.

Another example of inconsistencies between Notified Bodies is demonstrated by how MEDDEV 2.7/1 (http://bit.ly/ER6aMEDDEV) is enforced. This document guides manufacturers on how to perform clinical evaluations. Some Notified Bodies, especially the Notified Bodies under MHRA’s jurisdiction (see the list above), are systematically reviewing the content of clinical evaluations against the MEDDEV guidance. However, other Notified Bodies continue to verify only that a clinical evaluation exists. Differences between Notified Bodies in how they enforce this MEDDEV is less pronounced for Class III devices, where clinical studies are expected. However, this may be due to the lack of clinical expertise at some Notified Bodies.

The European Commission began a pilot program in 2013 for conducting joint audits by Competent Authorities of Notified Bodies to ensure that there is consistency between the Notified Bodies, and how the Competent Authorities enforce regulations (http://bit.ly/Europa-press-release-24-9-2013). Some of the other changes, such as conducting unannounced audits of manufacturers and their supply chains, are being implemented this year (http://bit.ly/Unannounced-Audits).

Due to the ongoing debate between the European Council and the European Parliament over the draft of the proposed European Medical Device Regulations (http://bitly.com/EMDR-Frankenstein), the issuance of new and revised MEDDEVs has essentially stopped. When the European Medical Device Regulations (EMDR) are finally approved, the medical device industry can expect to see the content of the MEDDEV guidance documents to be superseded by new requirements in the EMDR.

Are MEDDEVs Required or Optional for CE Marking of Medical Devices? Read More »