KlokUpdate 27-NOV-2019: The EU commission issued a second corrigendum, which upon acceptance by the parliament will give manufacturers of Class I medical devices 4 years extra to bring their clinical evaluation in order, putting them in the same position as the other medical devices with a valid CE certificate.

With only half a year left until application, the implementation of EUDAMED delayed with 2 years, and slow progress on implementation of acts and guidances, there are calls for and rumors on extension of timelines of the EU MDR. But does that actually mean that medical device manufacturers have more time to bring their clinical evaluation in order?

Under the MDR all devices will require a Clinical Evaluation with clinical evidence

“appropriate in view of the characteristics of the device and its intended purpose”

including Class I devices.

Medical devices with valid CE certificates can be placed on the market under the current EU Directives as well as the new regulation during the transition period of the MDR. This means that CE certificates issued under the current Directives will remain valid for a period of four years post date of issue, so until 25th May 2024, unless there is a significant product update (then a clinical evaluation per MDR is needed).CE

Does that mean that for devices with a valid CE certificate there is plenty of time to update their clinical evaluation? The answer is that that depends on the device and the concerning clinical evaluation plan, since under the current directives manufacturers are required to actively update clinical evaluations

“.. when the manufacturer receives new information from PMS that has the potential to change the current evaluation; if no such information is received, then at least …. every 2 to 5 years if the device is not expected to carry significant risks and is well established”

so best case the manufacturer with devices in this category has time until the certificate expires.

LaidBackA laid back attitude towards product clinical evidence collection, however, is not advisable, since these manufacturers are in the fortunate situation they still have time to gather their own clinical evidence in a postmarket setting, which currently (changes are in progress everywhere though!) is still less complex than in a premarket setting, and might be a necessary evil since the equivalence pathway has become much harder under the MDR as technical, biological, and clinical

“characteristics shall be similar to such an extent that there would be no clinically significant difference in the clinical performance and safety of the device. Considerations of equivalence must always be based on proper scientific justification. Manufacturers must be able to clearly demonstrate that they have sufficient levels of access to the data on devices to which they are claiming equivalence in order to justify that claimed equivalence.”

More problematic is the situation for

class I medical devices since they have no CE certificate and will have to comply with the MDR and update all technical information including clinical evidence by May 26, 2020. Manufacturers of Class I devices may still self-certify, as long as MDR requirements are satisfactorily met, BUT an extra complicating factor is that several Class I devices have been up-classified to Class IIa, IIb or even Class III (including some health apps), SleepApnoeAppand the requirements with respect to pre- (and postmarket) clinical evidence are more strict under the current directives as well as the MDR.

Now, news is circulating for some time now that a second Corrigendum is in preparation, potentially introducing a transitional period for up-classified class l devices, including class I reusable devices, but, although projected for this month, thus-far unconfirmed as far as I am aware. So manufacturers better not bet on that, and, products with a valid CE certificate aside, all devices are still in the same boat as far as timelines for updating their clinical evaluation are concerned.

In conclusion, do medical device manufacturers have more time to update their clinical evaluation? Thus-far the answer is no, as nothing changed in that respect since the clarifying interpretation of the MCDG in beginning this year, and for the majority of devices the deadline of May 26th, 2020 still applies. So at this moment the key question is more whether 6 months will be enough to build or strengthen the clinical evidence base, if not already started working on it? For a full blown clinical investigation it typically will be too short (also refer to a previous post addressing time needed for a clinical trial), but when using alternative sources for your clinical evaluation it might just be tight, and key is to act NOW.

Feel free reaching out in case of questions regarding the above, or support needed concerning your clinical evaluation.


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beach-landscape-sea-coast-water-rock-917958-pxhere.comThe medical device regulatory environment in Europe is moving, but not always as timely and as clear as one would wish, certainly not from clinical perspective. The

MDR/ IVDR Rolling plan

has been updated and mentions clinicals a few times, and I find the part on Eudamed stating that

“It is estimated that modules for clinical investigation and market surveillance might be only partly or not at all available at the time of application of the two Regulations (due to workability issues) but few months after.”

a little disturbing, especially as that will not only affect new clinical investigations, but also the ongoing studies: Among other things the MDR states that clinical trials that have started under the MDD prior to 26 May 2020 may continue, but also that reporting of serious adverse events and device deficiencies shall be done according the MDR. Meaning that from 26 May on these events need to be reported via Eudamed per Article 73 (e). So, althought progress has been made drafting the functional specs for Eudamed, I am not sure where this will lead us.

MDCG guidances

More MDCG guidance documents have been published and of particular interest from clinical perspective is the one on the clinical evaluation consultation procedure, with an (not legally binding) interpretation of the 3 criteria exempting devices from the clinical evaluation procedure with expert panels, and especially the one regarding

“new devices designed by modifying a device already marketed by the same manufacturer for the same intended purpose…”.

The interpretation is that “a device already marketed” cannot be intended to refer to a device already marketed uniquely under the new Regulation, and so, as Erik Vollebregt put it

“scrutiny is only for devices that are new at the time of the conformity assessment application for the MDR”,

which will be of great help trying to get some control over the workload of the expert panels.

And last there is the never ending story of the


Althought May is fighting it untill the bitter end, a no deal Brexit seems closer than ever, and the potential impact for those using or dealing with medical devices, and for UK patients requiring imaging and radiotherapy can be substantial.

Since UK Notified Bodies and competent authorities will no longer be recognized by the EU, medical devices and in-vitro diagnostics no longer can be brought to the EU market via UK: devices which enter the EU via or from the UK will be handled as import from a third country with all related consequences.

Patients with cancer in the UK are expected to face substantial challenges accessing the best care, as among other unfavorable developments, hospitals no longer carring out their own PET-CT services, deliveries of radiopharmaceuticals delayed and certain patients prioritised over others.

In conclusion,

the medical device environment in Europe is changing, with several moving parts and many uncertainties for manufacturers, users, and patients. We should keep in mind, thought, that most changes have been initiated for a better protection of patient safety.

Feel free reaching out to discuss any of the above or other aspects of the medical device clinical pathway in Europe.


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hamp-guidelinesThe MDR as well as the current version of MEDDEV 2.7/1 reference ISO 14155 as GCP standard for medical device clinical investigations. Indeed, the 2011 version, but the third edition is in the making, so it can be good to familiarize yourself with what is coming our way, and anticipated for this year.

The current draft has some interesting additions, such as more attention for the relationship of clinical studies with device risk management procedures, and the product developmental stages. Besides that I find the addition of risk-based monitoring, and more extensive guidance on statistical considerations worth noticing.


The clarification of the relationship of the different types of pre- and post-market clinical studies with the product development stages and the applicability of ISO 14155 (Annex I), in combination with the refined scope and definitions, indicate that the scope has widened; Such that the new version of ISO 14155 includes post-market clinical studies, interventional as well as non-interventional.


The scope indicates that the “principles set forth in this document also apply to post-market clinical investigations …”, and the definition of the investigational medical device (medical device being assessed for clinical performance, effectiveness or safety in a clinical investigation) has a note that

“this includes medical devices already on the market that are being evaluated within their intended use in a post market clinical investigation (interventional or non-interventional).”

Also the applicability of ISO 14155 as addressed in Annex I, indicates that “Depending on the clinical development stage and the type of the clinical investigation design, the principles of this standard be applied in full or in part”, and significant deviations should be documented.

So all very much in line with the upcoming MDR, that already specified in article 82, that also other than the regular pre-market clinical investigations should comply with the basic regulations of GCP.

Risk-based monitoring

New is the section on risk-based monitoring, in the chapter regarding the monitoring plan, that parallel to the current trends to reduce the study (budget) burden due to on-site monitoring visits, leaves more room for a combination of on-site and remote monitoring. Very different from the current version that allows for remote monitoring in “exceptional circumstances” only, the current draft version specifies that

“Centralised monitoring is a remote evaluation of accumulated data and compliance to provide additional monitoring capabilities that can complement or reduce the extend and frequency of onsite monitoring.”

Interestingly in this section, there is also specific attention for the (local) data-protection regulations, which to my opinion was pretty much covered in the current version in the section on the Informed Consent, but apparently there was a need to re-emphasize this essential aspect of clinical trial data collection and review following the implementation of the GDPR in May 2018.

Risk management

safety helmetOne of the most challenging aspects of a clinical study concerns the collecting safety data and the ongoing need for alignment with other teams/ departments involved in the review and follow-up of ADE’s/ incidents and device risks, and I am happy seeing the extra attention the new version of the ISO 14155, referencing ISO 14971, is paying to the performance and updates of risk management activities throughout the full cycle of a clinical study (chapter 6.2 and the new Annex H):

“(Residual) risk(s) to the study participant due to the investigational device and/ or the clinical procedures required by the study protocol shall be weighted on an ongoing basis versus potential benefit …”

Also interesting in this respect is the specific attention for investigational medical device training for users. An important – often underestimated – aspect of medical devices, that again should be ongoing throughout all phases of the clinical trial to minimize risks for the study participants involved. Last but not least, the new draft version includes more detailed guidance on the

Statistical substantiation

MEDDEV 2_7_1 Rev4_stats tablefor the study design. Similar to what we saw with MEDDEV 2.7/1 Rev 4 (also refer to my previous blog post on this), there is much more attention for the statistical substantiation of clinical trials, and the statistical section in Annex A (A7), has been more than doubled. Indicating the leaning towards a higher level of evidence studies with a more solid basis, creating additional challenges for observational studies and leaving less room for exploratory studies.


In conclusion, it looks like with the third edition of the ISO 14155 we are heading for Medical Device GCP with a broader scope and more guidance on key aspects such as risk management, monitoring and statistics. Very much in line with the overall developments in the EU medical device clinical trial environment, and creating – budgetary – opportunities as well as challenges for SME’s.

Feel free reaching out in case you want to discuss any of the above or otherwise.


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Happy New Year

From a medical device clinical evidence perspective, we are looking back on a turbulent 2018 and forward to an exciting 2019.

Highlights of 2018 included,

Looking ahead to 2019,

Please feel free reaching out in case of any questions regarding this post, or when you are looking for support with your medical device clinical evidence strategy.


Happy New Year!

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