CE Marking: 3 Biggest Challenges for US Companies

Rob Packard

Ship & Print Your FDA eCopy

October 2015

3 min reading time

If you have a moderate risk device you probably will submit a 510(k) before applying for CE Marking, because some of the requirements for a technical file are more challenging than European requirements.

Risk Management File
The FDA only requires documentation of risk management in a 510(k) 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 510(k). If a product is already 510(k) 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

Clinical Evaluation Report (CER)
The FDA does not require a CER, and up until 2010 only some CE Marked products were required to provide a CER. In 2010 the MDD was revised and now a 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 510(k) 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 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 CER and failure to include a copy of the articles reviewed in the CER. These requirements are outlined in MEDDEV 2.7/1 (http://ec.europa.eu/DocsRoom/documents/10324/attachments/1/translations/en/renditions/native), but the amount of work required to perform a clinical evaluation that meets these requirements can take 80 hours to complete.

PMS & PMCF
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 PMCF studies or a justification for why PMCF is not required. The biggest mistake I see is that manufacturers refer to their PMS procedure as the PMS plan for their product family, and they say that they do not need to perform PMCF because the device is similar to several other devices on the market.

Manufacturers need to have a PMS plan that is specific to a product or family of products. The PMS procedure needs to be updated to identify the frequency and product-specific nature of 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 PMCF studies. Even products with clinical studies might require PMCF, because changes to the device, accessories and range of sizes may not be covered by the clinical studies. MEDDEV 2.12/2 (http://ec.europa.eu/DocsRoom/documents/10334/attachments/1/translations/en/renditions/native) provides guidance on the requirements for PMCF studies, but most companies manufacturing moderate risk devices do not have experience obtaining patient consent to access medical records in order to collect PMCF data–such as postoperative follow-up data.

Medical device manufacturers are challenged by several other requirements when they are applying for CE Marking. Which requirements did you find to be the most challenging?

source: https://www.linkedin.com/groups/2070960/2070960-6057579430275006467

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Posted by Rob Packard

Asked on October 7, 2015 12:00 am

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like 14 comments

	Private answer Arthur Brandwood Oh and a post script. make sure you include the search terms and inclusion criteria in your report. The reviewer will sometimes want sufficient information to be able to replicate the search if required. Marked as spam like Report spam
	Private answer Arthur Brandwood Quite separately - a good clinical evaluation is not just a European thing. It can be enormously helpful in a 510(k) in addressing equivalence with predicate device(s). After all - that's what a literature review is partly doing - looking at (al the) other devices in the market and their performance as it is relevant to your device. If you look at the new regulations in China - it's really interesting that their Clinical Evaluation Report format actually includes a comparison table with predicate devices which is closely based on the FDA's 510k comparison table approach. Marked as spam like Report spam
	Private answer Definitely the clinical evaluation report, for low risk devices. As you clearly identified the absence of literature for this type of device is critical, and the clinical investigation not justified...quite tricky Marked as spam like Report spam
	Private answer Marcus Gould The unpredictable timelines when dealing with the competent authorities to obtain the positive opinion required for the safety, quality, and usefulness of ancillary medicinal substances. These timelines are difficult to work with when the competent authorities own guidelines are not followed by the competent authorities! Marked as spam like Report spam
	Private answer Pedro Fregoso Post-market clinical follow-up (PMCF) will be by far the most challenging requirement for the Medical Device Industry. New requirements in Risk Management and Clinical definitions will require a comprehensive review and renovation of current business practices by Medical Device Manufactures. Marked as spam like Report spam
	Private answer Arthur Brandwood Hi Rob - interesting post - thank you. Couple of follow on points on the CER: The requirement for clinical evaluation was always there for all devices in the directives from 1993. However it was contained in a very brief few words which was, shall we say, re-interpreted by manufacturers and notified bodies to be not really required for low risk devices. The 2007 revision of the MDD fixed that - adding several paragraphs of clarification (if that's not an oxymoron) that clinical evaluation is required for every device irrespective of class and that the higher risk devices were expected to have stronger evidence. The current draft European regulations go one step further and make the default position for Class III devices to be direct clinical trial data, unless a credible justification for an alternate approach can be provided and accepted (and Notified Bodies are likely to be very conservative about such arguments). With regard literature based evaluations, we see so many manufacturers fall down because they haven't got a pre-defined search strategy and they cherry pick only the favourable literature. Australia's TGA, which uses a regulatory system very closely based on the European Directives, has been particularly strict on this for years. They sort of see Europe as catching up :) The minimum expectations for a properly done clinical literature review should be : * Search databases defined in advance and justified for applicability and relevance of coverage. * Search terms defined in advance and justified for relevance and completeness. * Exclusion/inclusion criteria defined in advance and justified. These are not the same as search terms. Search terms generate the list of retrieved articles. Inclusion criteria allow you to inspect the article titles and abstracts and cull that list down to articles of actual relevance to the evaluation. * Articles must be reviewed and considered if they meet the criteria - in other words - no selection of just the favourable articles. If there are articles unfavourable to your cause they must be considered and addressed in the review. In other words the review must be comprehensive and balanced. There's good odds that the reviewer will know about the unfavourable stuff anyway so it's a really bad idea to ignore and hope they don't notice. * In Australia the TGA have always insisted on the literature review and broader clinical evaluation report be reviewed and endorsed (or originally authored) by a relevant clinical expert - i.e. an experienced clinician who would be familiar with the use of the device. Expect to see this kind of expectation appearing in more jurisdictions. The clinician doesn't always have to be a doctor. We have prepared CER's for dressing packs where the expert was a Nurse and equipment for use in ambulances where the expert was a paramedic. Arthur Marked as spam like Report spam
	Private answer Marie Suetsugu Dear Robert, Am I right to understand that you mean 'some of the requirements for a technical file are more challenging than American requirements' in the first paragraph?? Marked as spam like Report spam
	Private answer Robert van Boxtel @Arthur: even "better" practice: Start with the literature evaluation early in the design process. It will Ensure that a more clear picture on user requirements can be collected. Once the product reaches the stage of market approval (with or without clinical study), you only need to update it for the newest publications. Marked as spam like Report spam
	Private answer Arthur Brandwood Very good point @Robert - exactly right - this stuff needs to be part of the design inputs cycle Marked as spam like Report spam
	Private answer Armin Beck All of very good points but my first choice would be the CE-Mark rather trying to get a 510(K). The clinical evaluation report is not an big issue as some of the data can be obtained during bench testing and as Arthur mentioned the MDD required clinical evaluation. One of the biggest advantage of CE-Mark is the "intended use" The EU authority's do not demand a specific "Intended Use" The manufacturer has the freedom vs the FDA. I Have dealt with the FDA many time and had to change the IU based on their requirements. That make the process much more complicates especially from the clinical point of view. Second, I like to give you a theoretical but realistic scenario. Company A an promising startup is ready to file for market clearance preparing the 510(K) . The burn rate is 250K a month . The FDA take 3 month to answer and comes back with a lot of questions. It take the company to fix the issue another 4 month. The reply will be submitted to the FDA and company A received clearance after another month Now 8 month have past and we lost just 2 million $. Company B files for CE-Mark with an expedited review process. The NB auditor shows up at the company and spend 3 days with the company to review the TF. All issue are solved during the audit and company get the CE-Mark certificate 2 weeks later. Not a bad deal. Armin Marked as spam like Report spam
	Private answer Clarisa Tate Thank you for the post and to everyone that responded. Everyone's made a very good point. I think the hardest are the clinical evaluation and post-market studies or justification for lack thereof for low risk devices. Most studies just use these low risk devices as part of a diagnosis or a procedure. They aren't necessarily studying the actual product or how the product changes have affected the procedure so it can be, as a poster here said, "quite tricky". Marked as spam like Report spam
	Private answer Robert van Boxtel @Armin: You raise an interesting point: "The clinical evaluation report is not an big issue as some of the data can be obtained during bench testing " Currently, with quite a number of NB's, you cannot use bench testing results in the clinical evaluation, as clinical evaluation is determined to be evaluation of clinical data. Hence only clinical data can be evaluated. Therefore, your approach on that might not be accepted so easily anymore. Additionally, the NB's do require a specific intended use, but are sometimes less strict on indications for use within the intended use. In other words, the evidence of one indication for use can serve as a base for all, falling under the intended use. Lastly, more and more NB's will not anymore allow initial technical file reviews onsite as part of the audit. Hence the Q&A encountered with at the FDA will be also becoming more common practice with NB's. Summarizing: you burn rate calculation, clearly in favour of the EU, is now more and more also visible and applicable to the EU situation, in the aftermath of PIP implants, Hernia Meshes, MoM hips, pacing leads etc. Most importantly, be aware for whom you are developing: don't take shortcuts there, it is not in the patients benefit. Marked as spam like Report spam
	Private answer Arthur Brandwood @Robert @Armin Notified Body audits - particularly for a NEW manufacturer are usually two stage these days. First stage is an initial review - where they do a site visit and an overview of the QMS and Tech. File, raise any big issues, note anything not yet in place and then go away and come back 6 weeks later to do the real thing. That process allows particularity a new starter to get last minute things fixed up and address any (manageable) deficiencies. With expedited review - it's true that some NBs offer this for an additional fee - but it usually applies to the off-site review of the Technical File - and not to the on site audit. So in summary - I agree the NB process is far more than 2 weeks - in my experience it is usually around 3 months for medium to low risk devices. It can be longer for higher risk, it can be shorter and it can be reduced by paying more for expedited processing. Whether it's quicker or slower than 510(k) ultimately will still depend on the device type. Marked as spam like Report spam
	Private answer Alan To this group and discussion thread may be of interest to you. Marked as spam like Report spam

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