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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 new 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 revision 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 4 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provided in the appendices, while the 12-page clinical evaluation checklist that was provided in revision 3 has been replaced by one page of bulleted items for Notified Bodies to consider.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 on the basis of 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 5 years is 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 5 years of experience or 10 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

There are seven steps that 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 4 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) important technical file and 510k submission differences: 1) the risk management file, 2) the clinical evaluation report, and 3) the post-market clinical follow-up report.

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

3 important technical file and 510k submission differences

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

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

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

Risk management file for technical file and 510k submission

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

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

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

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

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

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

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

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

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

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

Procedures & Webinars

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

Posted in: 510(k), CE Marking

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Regulatory pathway document creation–a case study

This regulatory pathway case study is provided by Medical Device Academy 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 a 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 3 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 for 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, while 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 identifying the testing requirements for safety and efficacy. If the FDA has a 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 a 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 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 modified, a CER was required 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. Key elements of your search protocol should include: which search databases you selected and why, intended use and indications for 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 include the type of clinical study, the number of patients, the study design, etc.

Qualified Individuals

In order 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 design of the device or similar devices. Another person should be an expert in performing literature searches to ensure that the review of literature is comprehensive. Finally, the team needs at least one person with a clinical research perspective in order to critically evaluate the clinical data. 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 persons resume or curriculum vitae. Omission of these qualifications or the failure to rely upon clinical experts to perform a review of 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 important 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. If you are not sure which databases to choose and why, this is an indication that you need assistance with literature search methodology. This is typically part of the process for teaching doctoral candidates how to prepare for writing their dissertation and therefore academic credentials of the individuals contributing to the post-market surveillance activities is relevant.

Selection of Key Words

Often certain key words are more common in the title of clinical study articles than others, and these key words can help narrow the number of literature search results dramatically. Therefore, it is recommended to perform some preliminary searches with different key words in order 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 key word 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 mentions 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 prior to conducting the clinical evaluation in order to identify the most likely risks associated with the device. Each of these risks should be specifically mentioned 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 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 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 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 is 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 exactly the same justification of biocompatibility for 510k submissions as they were now submitting for their technical file. They were providing a one paragraph description of materials used and referencing the ASTM specification for implant-grade titanium. Both clients already had CE Marking for similar devices, and the wording of the justification for not conducting biocompatibility testing on the full device was identical to the previous submissions.

“Justifications are no longer permitted”

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

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

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

FDA requirements of biocompatibility for 510k submissions

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

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

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

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

New Draft Biocompatibility Guidance from the FDA

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

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

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

Technical File Differences for Bioiocompatibility

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

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

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

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

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

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

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

Posted in: 510(k), CE Marking

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Selecting and Changing the European Authorized Representative

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

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

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

Why your distributor is not a good 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 Authorized Representative.

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

Primary Responsibilities

The EU Authorized Representative has two primary responsibilities:

  1. Complaint handling
  2. Registration of CE Marked devices

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

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

Posted in: CE Marking

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Status of the European Medical Device Regulations?

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

MudI 600x334 Status of the European Medical Device Regulations?

The picture above is not a picture of people on their way to the local maple sugar shack, trying to get a car unstuck during mud season in Vermont. It’s actually a photo of paid actors reenacting the European negotiations for a 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 own blog posting. The best guess anyone has is that we might have a final version released next year in Spring 2016. It’s only 2 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, but this list includes a number fundamental principles that could dramatically change the nature of medical device regulation in Europe. Our expectation is that many of these issues will be resolved with a compromise of some sort, but I suspect every medical device manufacturer with a CE Mark will be extremely busy from 2016-2019 revising their procedures, technical documentation and training personnel on the new European Medical Device Regulations.

 What Should You Be Doing to Prepare?

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

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

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

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

Bogs Status of the European Medical Device Regulations?

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CE Marking Approval of a Medical Device (Case Study)

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

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

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

I identified three potential device classifications: 1) Class 1 as per Rule 4 (a non-invasive device which comes into contact with injured skin, if the device is intended to be used as a mechanical barrier, for compression or for 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 best practices in European legalese. If you want to make something almost unintelligible, copy Article 11. If you want to understand this stuff, a flow chart of the various routes to conformity is as good as it gets (still hard to understand, but fewer words). The following simplified table is what I use in my CE Marking webinar:

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

What you need to know…

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

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

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

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

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

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

In all, I estimate that the overall timescale for completing this project is about 60 days–not including review by the Notified Body. Therefore, I suggested that the client obtain a quotation from their registrar for an Annex V Certificate. In addition, I suggested hiring a consultant from Medical Device Academy to help them with preparation of a Clinical Evaluation. Prior to 2010, Clinical Evaluations were only required for high-risk devices. As part of the new MDD, clinical evaluations are now required 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 were 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 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 (mailto: rob@13485cert.com). We have standardized procedures to meet each of the requirements in the European Regulations and a couple of webinar recordings that explain both the Medical Device Directive and how to create a technical file or design dossier.

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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.

unannounced audits Notified Body Unannounced Audits Have Begun

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 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 Member States will use compliance with the “recommendation” for unannounced audits as one of the criteria for deciding which Notified Bodies will retain their status when the new European Medical Device Regulations are 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 primary targets for unannounced audits are unlikely 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, but 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. In order to ensure that auditors are able to 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 designing similar 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 expect 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 a three-year period–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), but 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 July 18.

Posted in: CE Marking

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