IVDR AMENDMENT ADOPTED: HAPPY NEW YEAR!

Set to apply from May 2022 on, the IVDR proposed progressive roll-out has been adopted by the EU as a very welcome Christmas gift.

Essential to realize thought is that the amendment does not change the requirements of the IVDR but only extends the implementation for certain devices. New devices or CE-marked devices not requiring NB involvement must still meet the 26-May-2022 deadline, and the requirements on the performance evaluation still stand, so the IVDR rollercoaster will soon take off!

So what is the challenge?

Referencing the amendment, we are moving from a situation where about 3300 IVD’s require NB involvement for their conformity assessment to a situation with over 24 000 requiring so. This while at the same time the number of NBs went down substantially, so there is a substantial shortage in resources in this respect.

But is that the only issue? Based on several conversations lately, and looking at this from a clinical perspective, we are facing another one, and that concerns the

performance evaluation,

or rather the lack thereof. The performance evaluation is meant to show that any (clinical) performance claim is subtantiated by sufficient qualitative evidence, and that the device performs as intended. Given the upclassification of so many devices, however, multiple manufacturers are new to or relative unfamiliar with this process, and I cannot but emphasize enough that they shall

“… plan, conduct and document a performance evaluation”

per Article 56 and Annex XIII of the IVDR, and that NBs will review

“… manufacturers’ technical documentation, in particular the performance evaluation documentation”

So a performance evaluation plan should be created, that includes key aspects such as

• the device with its performance claims (accuracy!)
• the target patient group(s)
• a justification as to why certain analytical, clinical, or other performance requirements are not considered applicable, or when required,
• the data that shall be generated in (clinical) performance studies, and
• the PMPF plan.

Especially on the last 2 bullets there appears to be some confusion, but let me help you out of your dream: a performance evaluation is NOT the same as a (clinical)

performance study

(or investigation, or trial). Studies are a way to generate the data needed for the evaluation, and in case of IVD’s we have

• the analytical performance studies that typically shall always be performed to generate data on the device’s analytical performance, and
• the clinical performance studies that shall be performed, unless due justification is provided, to generate data regarding performance in clinical practice.

When necessary to substantiate device performance (even more so under the IVDR), such studies need to be conducted in line with international ethical and regulatory guidance, such as the Declaration of Helsinki, ISO 14155 (GCP for medical device on human subjects, and be aware that the IVDR references an outdated version!), and ISO 20916 (see flow chart).

Unfortunately at this stage the amount of

EU guidance documents

on the performance evaluation under the IVDR is limited in spite of the nearing deadline. As a starting point, however, and in line with the IVDR

“… guidance developed for in vitro diagnostic medical devices at international level, in particular in the context of the Global Harmonization Task Force and its follow-up initiative, the International Medical Devices Regulators Forum, should be taken into account …”

we do have IMDRF guidance (pretty old thought!) and the COVID-19 TEST MDCG that was published last year. So besides Annex XIII, there are tools on the performance evaluation process, and indicating what steps should be taken and documented. With respect to

COVID-19 diagnostic devices

and press release on the adoption of the IVDR amendment, I found Stella Kyriakides’ comment that

“The pandemic has at the same time highlighted the vital need for accurate diagnostics and a resilient regulatory framework for in vitro medical devices. The amendment of the In Vitro Diagnostic Medical Devices Regulation will ensure that crucial medical devices, such as COVID or HIV tests, continue to be available and safe” 

quite interesting: While, indeed, the pandemic emphasized the need for a smooth functioning regulatory system, to me it also illustrates – again – some of its shortcomings. Referencing Ines’ recent blogpost on this topic, COVID test devices have substantial flaws for multiple reasons, but in light of the performance evaluation I find it frustrating that one of the reasons is that devices have been benchmarked with symptomatic people rather than a-symptomatic ones (wrong target patient group!). This while at the moment they are often used by a-symptomatic people.

In short,

there is a lot of clinical work ahead of us ensuring performance evaluations for the IVD’s are in order and substantiated by adequate and qualitative clinical evidence. If not started to date, you better start preparing yourself right now, because the deadline is closer and performance studies take longer than you think, while the rollercoaster is about to take off.

Feel free reaching out in case of questions or support needed, and in the meantime I wish you a good and above all healthy New Year!

Annet

As updated 05-JAN-2022

COVID-19 SELF TESTS – WHAT ARE THE RESULTS SAYING?

Earlier did a COVID-19 self-test, a test that conform the EU MDCG 2021-2 guidance has instructions for use (IFU) that should be

“complete and precise, including aspects such as: the intended user, the target population, window between infection and antibody detection, result interpretation (including limitations of interpretation)” etc, etc

… but now I am curious what the (negative) test results are telling me?

1. Am I truly not infected with SARS-COV-2 or 1 (the test is not differentiating!), and is it safe to go out and visit my parents, OR
2. am I the unfortunate one falling through the cracks, since COVID-19 tests are not 100% watertight (self-test or not), OR
3. did I mess-up the test procedure (incorrect swabbing – too deep or too shallow, shaking the tube the wrong way, waited too short or too long reading the results, etc), OR
4. was I not the correct person to use the test (not sure when my sore throat started), and should I have waited until I had more convincing symptoms?

Maybe it is me, but especially with respect to the latter I find the IFU extremely confusing:

The self-test I used is meant for people that have symptoms less than 7 days, is NOT meant for people with CORONA symptoms, AND can also be used for asymptomatic people … HUH? … Given I did not have any clear symptoms, and the self-test has been validated on symptomatic people, I, indeed, may not have been the right person for this test, but then WHO IS?

Since besides the indication there are multiple other factors (the above is just a short list, so refer to Ines’ blog-post on this topic if interested to learn more), including translation of study results into daily practice, that may affect the test results, there unfortunately is no clear answer to my question: The chance that I am infected with COVID-19 is just lower than before the test, but to what extent remains a ?

Besides that, I would like to call out to those involved in the performance evaluations of COVID-19 tests: Can you, PLEASE, make sure that the IFU, besides that it is complete and precise, also is understandable for any intended (lay)user to avoid any misunderstanding?

Annet

THE NEW ISO 14155: WHAT CHANGED IN THE END?

With the updated references of harmonised standards for medical devices, ISO 14155: 2020 is THE GCP standard for medical device clinical investigations, and since as of May 26^th 2021 the MDR fully applies you may want to familiarize yourself and your team with the changes to ensure proper clinical data collection in line with this standard.

In a recent presentation you can find some highlights on the main changes as well as differences with ICH-GCP:

20210413 nvfg acs iso14155 13_apr2021 from Annet Visscher

The new version has some interesting additions, such as more attention for the relationship of clinical studies with device risk management procedures and the product developmental stages, but also for risk-based monitoring, and guidance on statistics.

Scope

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, illustrate the widened scope; Such that the new version of ISO 14155 includes guidance on post-market clinical studies, interventional as well as non-interventional.

The scope indicates that the principles set forth in the standard are also intended for post-market clinical investigations and software medical devices considering the nature of the clinical trial, 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 that significant deviations should be documented.

So all very much in line with the MDR, that specifies in article 82, that also clinical studies other than the clinical investigations to establish and verify performance, clinical benefits and/ or clinical safety of the device should comply with the basic regulations of GCP.

Risk-based monitoring

New is the section on risk-based monitoring, that parallel to the current trends to reduce the study (budget) burden, and, following the corona pandemic, to reduce contact frequency, leaves more room for a combination of on-site and remote monitoring. Very different from the old version that allowed for remote monitoring in “exceptional circumstances” only. The 2020 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.”

Note that centralized monitoring is different from remote source data verification, which generally speaking is only allowed when justified and currently is limited to the corona pandemic period and/or pseudo anonymized data (also refer to my other blog post on this topic).

Interestingly in this section on the monitoring plan, there is extra attention for the (local) data-protection regulations, which to my opinion was pretty much covered in the previous 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

One of the most challenging aspects of a clinical study, I always find, 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 the clinical trial (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 essential, and 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, but also to ensure functioning of your device as intended.

Safety

Terms and definitions have been updated for better alignment with those listed in the MDR. The definition for serious adverse events for example now includes wording that these include a serious deterioration in the health of users, or other persons, and a new definition concerning a serious health threat has been added.

Furthermore there is an almost complete new section on adverse event and device deficiency escalation with more attention for corrective and preventive actions, as well as device deficiencies that could have led to a serious adverse device effect, if no action had been taken or circumstances had been less fortunate. The standard emphasizes that such events should be reported as thought an event occurred. Since, in addition, the standard emphasizes that any person with information that could impact subjects’, users or other persons’ safety, must inform the principal investigator and the sponsor of their concerns, and when combined with the enhanced attention for the clinical trial interrelationship with risk management, you may want to review and amend your safety data collection and review processes following this ISO update, if not already done.

Statistical substantiation

for the study design. Similar to what we saw with MEDDEV 2.7/1 Rev 4 (also refer to my previous blog post), 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.

Conclusion

In conclusion, it seems fair to say that with the third edition of the ISO 14155 we are dealing with a medical device good clinical practices with a wider 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 including the MDR with a better eye for patient safety, 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.

Annet

HOORAY: EU MEDICAL DEVICE CLINICAL TRIAL GUIDANCE ONE MINUTE TO MIDNIGHT!

You probably did read it by now, but just in case, herewith a few items that stood out for me while reading the EU Q&A for clinical investigations under the MDR ((MDCG 2021-6) published jst before the May 26th deadline.

Rumors

The guidance contains very helpful oversight on definitions on medical device performance, clinical performance, and clinical benefit, as well as an overview on the regulatory pathway for clinical investigations (or studies) under the MDR.

Given rumors were that non-interventional Post-market Clinical Follow-up studies do not fall under the MDR, I am happy seeing that per this overview these studies generally speaking are considered falling in the category ‘Other clinical Investigations’ (Article 82). Meaning that in principle such studies should comply with some provisions of Article 62 (legal rep, scientific & ethical review, informed consent, etc), as well as the applicable local regulations, unless you have a PMCF activity that does not meet the definition of clinical investigation, such as generic surveys and some specific types of data collection. Besides the questionable scientific value of with such tools, however, one needs to be very careful guarding data-privacy (health-care data are particularly sensitive under the GDPR), but then these activities may be justifiable for some of the lower (risk) class devices.

Mind you, you still need to check local regulations, and should be careful claiming to follow GCPs, since ISO 14155: 2020 has a different definition of clinical investigation, and states that if

”… requirements are less strict than the requirements of this document, the sponsor shall apply the requirements of this document to the greatest extent possible, irrespective of any lesser requirements…”.

Food for thought

With respect to MDR applicability,I am not sure what the guidance means to tell us with

“For clinical investigations of class I, or non-invasive class IIa or class IIb devices, it is necessary to check national provisions”?

In case of clinical studies we always need to check national requirements since local regulations tend to differ across the EU member states, and, again, conform ISO 14155 the sponsor shall apply the most strict requirements.

Or is the guidance meant to say that ‘For clinical investigations not performed pursuant to any of the purposes listed in Article 62(1), it is necessary to check national provisions’? Food for thought I think.

Definitions

As said above, the definitions (and applicability) for clinical investigations can be crucial, and it is good seeing attention for the definitions of Performance (ability to achieve the intended purpose), and especially Clinical Performance (leading to a clinical benefit) and Clinical Benefit:

“The positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient relevant clinical outcome(s)”.

Specifically patient relevant outcome(s) can be challenging for some devices (also refer to my previous blog on clinical evidence dilemma’s) since clinical evidence on patient benefit often is indirect, and patient outcomes such as a mortality, morbidity, and Quality of Life can be challenging due to endpoints depending on the underlying disease, and can require long-term patient follow-up.

In line with the adoption of

ISO 14155:2020 

back in April, the MDCG 2021-6 refers to the 2020 version of the GCP for medical device studies (instead of the 2011 version), for the different product development stages and related clinical investigations, but also for the content of your clinical trial report in ANNEX D, so it is key to familiarize yourselves with it’s content.

Last but not least, a few notes regarding

Ongoing medical device clinical trials

that started before MDR application: such studies can continue with the note that all (S)AE’s and device deficiencies that might have led to a serious adverse event “if appropriate action had not been taken” need recording, and that all SAE’s and device deficiencies occurring after 26th May 2021 need reporting according Article 80 of the MDR. In light of the fact that EUDAMED is not ready yet, reporting to National Competent Authorities can be done as before, but as a sponsor you are expected to review and update your protocols and procedures as needed. MDCG 2020-10/1 is also referenced for further guidance in this respect.

In conclusion, I think it is fair to say that although late the Q&A on medical device clinical trials is a helpful guidance with some room for interpretation and/ or debate.

Feel free reaching out should you be interested to discuss the above or any other aspects of the clinical evidence collection proces for medical devices.

Annet

MDR/ IVDR CLINICAL EVALUATION TOOLKIT; PART II

I am very happy that as of April, we have more time until the date of application of the Medical Device Regulation, as well as more clinical guidance to work with. In my previous post I addressed my observations on the guidance for the clinical/ performance evaluation of Medical Device SoftWare, in this one I will focus on the one for equivalence (MDCG 2020-5).

MEDDEV 2.7/1 REV 4

This guidance provides directions on the use of clinical evidence from equivalent device(s) for the purpose of the clinical evaluation. While highlighting and clarifying the differences, it uses MEDDEV 2.7/1 Rev 4 as a basis; which is great, since we are all familiar with that one and we updated (almost) all our clinical evaluations accordingly, right?

In fact for information on how to analyze clinical data from scientific literature it actually refers one to it, so we still need the current MDD guidance. Mind you, there is a conditional note though that

“In the event that the data do not meet the MDR definition of clinical data these are not clinical data and cannot be subject to data appraisal, analysis and evaluation for the purpose of providing clinical evidence”,

and given the MDR definition of clinical data, I wonder where that leaves us with clinical experience collected via physician testimonials or surveys; a tool we have been using to quite some extent the last few years to collect clinical experience in daily practice in a low-resource-consuming fashion.

Good thing is, that, similar to the MDSW clinical/ performance evaluation guidance, pending the development and publication of further MDR/ IVDR guidances, it seems a good strategy to continue using the existing ones including those from the IMDRF as long as they are in line with the MDR/ IVDR.

SAME

Also conform MEDDEV 2.7/1 Rev 4, clinical, technical, and biological characteristics need consideration for demonstration of equivalence to another device with respect to safety and performance. At first sight the same as before, but here the devil is in the details since instead of  similar some of the characteristics are explicitly mentioned as must be the same under the MDR. Especially the

BIOLOGICAL CHARACTERISTICS

are getting attention in this respect (3 pages!), and particularly noteworthy is the remark that

“the exceptions outlined in the MEDDEV 2.7/1 Rev 4, to NOT use the same materials are NOT  acceptable under the MDR”

(capitals are not mine). So for biological characteristic to be considered equivalent the equivalent device should use the same materials or substances in contact with human tissue or fluids. The guidance also stresses that since processing may affect the materials, the assessment should concern the final device.

On the clinical characteristics the guidance emphasizes that for equivalence the devices shall have the same kind of user (underlining that it makes a big difference whether users concern HCP’s or lay people due to their knowledge and competences), and that the devices should be used for the same clinical condition or purpose. That a

GAP ANALYSIS

needs to be performed within the context of a clinical evaluation is nothing new, but thus far this was to determine whether clinical data was sufficient to verify that the device is safe and performing. The current guidance adds in this respect (providing an insightful equivalence table as an example), that also a gap analysis has to be performed evaluating

“any clinically significant differences”,

and their possible impact on safety and performance (note that clinical significance is NOT the same as statistical significance, so obtaining expert input is essential here), but also that

“considerations of equivalence shall be based on proper scientific justification”,

telling me once more that showing equivalence is no longer a simple paper exercise, and one will not be able to get away with a simple statement saying that despite some small differences devices can be considered the same.

SUFFICIENT LEVEL OF ACCESS TO DATA

Another topic that received much attention since publication of MEDDEV 2.7/1 Rev 4 concerns the need for access to the technical documentation of assumed equivalent devices. Also here the MDCG 2020-5 guidance leaves no room for debate, and once more underlines that under the MDR a manufacturer must be able to demonstrate sufficient level of access to the data of the equivalent device, and that for Class III and implantables this means a contract must be in place with the manufacturer of the equivalent device allowing for ongoing access to the technical documentation.

MDR CERTIFIED

Moreover for these devices the guidance requires that the

“clinical evaluation of the equivalent device has been performed in compliance with the requirements of the MDR”,

and that therefore equivalence with a device CE-certified under the MDD or AIMDD is no option. Basically making it almost impossible to bring Class III or implantable devices to the EU market on the basis of equivalence, unless the equivalent device concerns a modified version of a device already marketed by oneself.

In contrast for devices other that Class III or implantable devices , the equivalent device does not need to be CE-marked as long as clinical data are collected in line Good Clinical Practices and data are transferable to the EU population.

CONCLUSION

So while happy at first sight with a flood of MDR clinical guidance being published lately (another one on safety reporting in clinical trials was published this week), the details bring us back to earth, making one realize that clinical evidence has to meet higher, tougher standards, and that the reversed Christmas tree of clinical evidence with equivalence as its base has finally been brought down.

Feel free reaching out for a discussion on the above, or in case you need support with your clinical evaluation or investigation.

Annet

MDR/ IVDR CLINICAL EVALUATION TOOLKIT; PART I

After a long period of waiting, several delays, and the MDR deadline without proper guidance hanging above our heads like the Sword of Damocles, as of end of April we have one more year until MDR date of application and a ‘flood’ of guidelines to work with.

So while keeping the clinical work on track as good as possible in the almost ‘fluid’ COVID-19 environment, I thought I’d give the ones regarding clinical evaluation a look.

At first sight there is not a lot of news, but a couple of things stood out from my perspective, especially since after a closer look they appear to give us a taste of the MDCG’s thinking and what we may expect from further guidance. In this blogpost I will address my observations on the guidance for the evaluation of Medical Device SoftWare (MDCG 2020-1), later this week followed by the guidance for equivalence (MDCG 2020-5).

IMDRF

Besides that MDCG 2020-1 addresses MDSW of all medical devices, including IVD’s, it is interesting to see that, although emphasizing that it “solely” applies to MDSW, this guidance uses IMDRF concepts as a starting point, such as N41. With several medical device guidances still pending, this gives us an idea of the MDCG’s thinking, and in the run-up to further publications it seems a good strategy to continue using existing guidelines at our disposal including the ones from the IMDRF.

SCOPE

The guidance includes a helpful table clarifying the clinical/ performance evaluation requirements in relation to intended purpose of the MDSW, indicating that MDSW with an independent medical purpose and MDSW with an intended purpose driving a medical device require an evaluation.

The scope also has a note specifying that

“If a software is driving/ influencing more than one medical device, an independent CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) is required for each foreseen and clinically viable software – device combination”.

So in case you are using certain MDSW for multiple medical devices, you are unfortunately not done with just one evaluation, which makes perfect sense since the MDSW should meet the intended purpose in a real-world environment (also refer to below).

Also of interest I find the acknowledgement that

“the final clinical outcome for the patient is dependent on further diagnostic and/or therapeutic options which could be available”,

in other words the clinical benefit for MDSW may be indirect and just lie in providing accurate information.

PROCESS

MDCG 2020-1 nicely (re-)visualizes the general evaluation PROCESS, which is the same regardless whether we are dealing with medical devices, in vitro diagnostics devices, or MDSW, and describes the 6 stages we are (supposedly) familiar with: planning/ scoping, data identification, data appraisal, data analysis within the context of the Essential Safety and Performance Requirements, reporting, and updating throughout the product life cycle.

SUFFICIENT

I am delighted seeing in this guidance we finally get a sense for what will be considered sufficient evidence. Something we have been waiting for for ages by now, and clarifying (at least for MDSW although it reads pretty generic with the exception of one example question) that the assessment of what is sufficient data should be determined based on answers to questions regarding the amount as well as quality. Example questions proposed include:

Sufficient amount

• Does the data support the intended use, indications, target groups, clinical claims and contra-indications?
• Have the clinical risks and analytical performance/ clinical performance been investigated?
• How big is the body of scientific evidence?

Sufficient quality

• Were the type and the design of the study/ test appropriate to meet the research objectives?
• Was the statistical approach appropriate to reach a valid conclusion?
• Were all ethical, legal and regulatory considerations/ requirements taken into account?

In fact no big surprises here, since the questions simply reflect aspects that we are supposed to take into account during the general process of appraisal and analysis of clinical data.

REAL WORLD DATA

With respect to the performance analysis, it is interesting to see the emphasis that is placed on the translation of MDSW performance into daily practice: in the section on technical as well as clinical performance it is emphasized that the manufacturer should verify and test that the MDSW meets the intended purpose in real-world usage, in the intended use environment and with the intended users, telling me that Human Factor testing  basically is the bare minimum that one needs to have data on.

A little misplaced seems the statement that

“CLINICAL EVALUATION of class III and implantable devices (MDR), shall include data from a CLINICAL INVESTIGATION unless the conditions of Article 61(4), (5) or (6) of the MDR have been fulfilled”.

While no-one will dispute that typically a pre-market clinical study is required for class III medical devices and implantables under the MDR unless it can be scientifically justified to rely on existing data, based on the text as it is right now, I find it puzzling whether this statement is meant to be applicable for MDSW, and, if so, for what type (stand-alone MDSW up-classified to class III and/or MDSW influencing a class III medical device?). I  anticipate  some clarification in this respect upon revision of this guidance.

CONCLUSION

To conclude this post, while at first sight this guidance seems a repetition of what we already know, and it indicates to be subject to revision upon the publication of other “horizontal” guidance for other devices that MDSW, it has interesting new elements worthwhile to take note of which are potentially also supportive for evaluations beyond the scope of this guidance.

Annet

COVID-19 CLINICAL EVIDENCE DOWNTIME: HOW TO MAKE USE OF IT!

To date numerous guidances, blogposts, webinars have been published addressing what one must and cannot do in the process of clinical evidence collection due to the COVID-19 pandemic (for overviews see here and here), and with this post I have no intention repeating that, but rather want  to focus on the things we CAN do and actually use this downtime to increase the quality of our clinical evidence base.

Clinical Evaluations

With my medical device background, I cannot help but address the fact that following the Coronavirus pandemic the MDR date of application is likely to be delayed with one year (mind you, the IVDR DoA still stands, with an even bigger clinical evidence challenge, or quoting Erik “another crisis in the making”), and as (hopefully) known, an important activity concerns (re)assessment and updating your device clinical evaluation(s). The extension of the deadline does not only give you more time to do a better, more thorough, job updating your clinical evaluation report(s) (after all, literature and database searches, and writing can still be done), but also, if recently discovered that your (accessible) clinical evidence base is too small (maybe the equivalence did not work out that well, or the available clinical data of the equivalent device is not as good as expected, or…, basically something you should have assessed much earlier), it gives you more time (3-6 months or so, also see below) to collect and process your own clinical data on the safety & performance of your device, and depending on the specific situation in a pre- or post-market setting.

Clinical Trial start-up

Over the years I have been mentioning that the clinical investigation start-up process is like getting a baby, didn’t I? Roughly the study start-up process will take 9 month from conception (idea) to birth (FPI) (anything faster thumbs up!), so when near to, or in the process of initiating a clinical trial, now is the time for a thorough discussion (video, phone, e-mail, …) with your (candidate) study PI’s, steering committees, etc, on the details of your study design and endpoints, write-up the corresponding documentation, and initiate the applicable EC/ IRB, R&D Committee, Competent Authority approval routes.

In absence of the usual pressure to get that done (in the current situation every-one including management will understand that FPI takes more time than usual), you now can take the time needed, thereby enhancing quality and reducing mistakes, and consequently the number of protocol amendments with related consequences in the course of the study.

Indeed, in the current situation EC & CA review takes more time than usual due to coronavirus trial priorities and people involved working remotely, but everyone is getting used to it by now, and the process is still ongoing (actually even better since processes are more tweaked towards fully digital submissions instead of using paper), so there is nothing to keep you from submitting your clinical trial package for review.

If well timed, you will be ready for study kick-off as soon as the pandemic is under control.

Clinical Trial execution

Excluding coronavirus related trials, the execution of clinical investigations and specifically patient enrolment has come to a grinding halt, and several companies actually put their trials for that reason on hold.

Provided there is study personnel available, however, participant visits can be converted from a  physical visits into a phone or video visit. In times like these study participants tend to be even more open to (extra) attention, and by phone you will be able to capture key parameters, obviously not with the details as when the subjects are on site, but for sure you will capture big events (Safety!), and with a little luck some other key parameters on your study, while also keeping the participants engaged for the remainder of the study when it picks up speed again when the pandemic is under control.

In addition, this to my opinion is also THE moment to apply and gain experience with risk-based and centralized monitoring. As mentioned in my preceding blog on this topic, options for remote SDV are  limited, especially when there is no dedicated study personnel able to give insights into study participant source data, but partially due to the fact that there will be little to no new data coming in, the timing for the other aspect of it centralized monitoring, i.e. checking for consistency, data completeness & trends, identification of sites with high (or low for that matter) PD and AE rates, is excellent. So review and (internally) discuss your study data and follow-up with the concerning sites, if possible, now, or otherwise right after the coronavirus downtime is over, thereby enhancing the quality of your data.

Clinical Trial closure

Being in the wrap-up phase of your clinical investigation, on-site close-out visits will hardly be possible at the moment, but (provided you have digital study files) you can still prepare for it by performing a TMF reconciliation, making sure all files are in order at sponsor’s as well as site’s end when performing the on-site close-out visit after the coronavirus downtime is over. Alternatively, when the reconciliation shows the files are in order, and site data review is finished, you could consider  performing the close-out by phone.

In case you are in the ‘fortunate’ situation that final  (or interim for that matter) and clean study data are available, you can also use the downtime to prepare the final/ interim study report and publication, and subsequently ensure the applicable regulatory bodies submissions/ notifications are done. The latter is still a neglected child as I unfortunately know from experience, in spite of the fact that (timely) reporting of the study results is an ethical and scientific duty partially imposed by GCP standards. So what better way to use this clinical evidence collection downtime than to write your reports when stuck at the (home) office?

Conclusion

In short, depending on the phase of clinical evidence collection process you are in, I believe there are several things we can still do to keep the processes reasonably on track. Limiting the amount of time lost and picking up speed once the pandemic is under control, and actually using this down-time to increase the quality of your clinical evidence base, working on your clinical evaluations, clinical study start-up documentation, performing centralized monitoring, and writing clinical study reports and publications where possible.

CORONAVIRUS AND CLINICAL STUDIES: WHAT TO DO?

By now the Coronvirus outbreak is affecting everyday life worldwide (see latest statistics Johns Hopkins University), and to avoid patient exposure or to reduce the burden on clinical services it also started impacting clinical trials; their execution, monitoring, and publications. Study staff re-allocated to clinical care or requested to stay at home, study participant enrolment and follow-up delayed to limit contact, and monitors being kept out of the hospitals.

With respect to clinical trial management more and more governmental guidance’s are appearing in a hard to keep up pace, indicating what is the best approach with respect to study suspension, protocol amendments, deviations, and study participant recruitment and follow-up. Suggesting for example changing participant site visits to phone calls or paper questionnaires by post where possible, keeping in mind that study participant’s safety has the priority.

In this blog post I would like to address another tool at our disposal for monitoring: Remote (or centralized) monitoring, which depending on the local situation and study security arrangements can be extremely helpful to keep the ‘clinical motor running’ as far as possible given the current situation.

BACKGROUND

Besides training, Site File review, etc., one of the main reasons for the on-site monitoring is proper source data verification (SDV), i.e. the process to ensure that data are verifiable, correct, and complete. On-site monitoring, however, represents at least 15% of the total clinical study budget, and digitization and evolving regulatory insights nowadays allow for remote monitoring (remote evaluation carried out at a location other than the sites at which the clinical study is being conducted),  as well. Although remote monitoring may not be considered the tool of choice for your current clinical trial and/ or described in the study monitoring plan, in the current situation it may be the best tool we have, keeping in mind that remote monitoring is not the same as

RISK BASED MONITORING,

although they do go hand-in-hand, because RBM allows for a lower than 100% SDV and it is extremely difficult to perform 100% SDV with remote monitoring and SDV (see below).

Key is to check whether your study allows for RBM, and what the monitoring plan says about remote monitoring. If it does include RBM, you may just need to adjust your timing or (temporarily) the degree with which you perform remote monitoring, or if it does not include RBM you may want to amend your monitoring plan, notify the applicable Ethics Committee on it (make sure to check their latest ‘Corona’ policy), and train your CRA’s. Especially do not forget the latter, since not all CRA’s are 100% familiar, yet, with remote monitoring procedures.

Good thing in this situation is that the

REGULATIONS

nowadays widely accept a risk-based approach for monitoring, and in parallel to the FDA, ICH-GCP, also the upcoming version of ISO 14155 allows for

“a combination of on-site and where justified, centralized monitoring, as appropriate”,

and see it as additional monitoring capabilities to complement or reduce the extend and frequency of on-site monitoring. So the ‘only’ thing to do is to ensure proper documentation and reporting to the applicable regulatory bodies (Competent Authorities as well as the Ethics Committees) of the ‘why and how’ to ensure you stay compliant with the applicable regulations.

While (temporarily) switching to remote monitoring, a few practical factors should be considered while performing remote monitoring, especially

REMOTE SDV

The study sponsor (eCRF or alternative), but ideally also the concerning sites (electronic patient files), should have electronic systems in place that are remotely accessible in a secured way. Working with a paper study and study staff at home will make remote SDV virtually impossible.

For proper SDV the CRA needs to be able to review the patient files. That tends to create challenges due to the fact that most of the hospitals in Europe do not allow for remote (so off-site) viewing of patient files by the sponsor due to (possible) data-protection issues, and in fact most of the Informed Consents do not include permission of sharing of personal not coded data outside the study site.

Since these limitations typically include blockage of web-based tools like WebEx, Skype, GoTo, etc., the best option we have in this respect is that study staff uploads critical coded and signed reports into the study sponsor’s electronic system (eCRF or alternative) making it accessible to the CRA for review. The obvious down-sides being that this places yet a higher burden on the site study staff (so they should not be re-allocated to critical clinical care!), and this concerns a highly selective review of a copy of the source. It would, however, to my opinion be the best option we have for the current situation besides suspending all activities, and is in line with a risk based approach with a reduced amount of SDV.

CONCLUSION

The regulations nowadays allow for combination of remote and on-site monitoring, and given the current situation it seems best to assess the situation for your clinical study, and (re) consider (temporarily) applying remote monitoring, while ensuring ongoing study participant’s safety and well-being, using a risk based approach for SDV.

Annet

2020 – THE 11th HOUR FOR THE MDR, ISO 14155, & OTHER EU CLINICAL MATTERS

 

Nothing could have been more illustrative for the medical device clinical trial environment in Europe  than the storms Ciara and Dennis in February. With BREXIT as a kick off, the Coronavirus spreading around te globe, the MDR deadline less than 3 months away, and a new version of ISO 14155 coming out shortly, 2020 for sure guarantees a stormy year for any-one involved in medical device clinical trials

Per 31-January BREXIT finally is a fact, but what that actually means for clinical trials with sites in the UK is unclear to say the least. Without any say from UK’s end, EU regulations such as GDPR and MDR still apply, at least for 2020, but at the same time MHRA published an updated guidance regarding medical device clinical investigations indicating that a clinical investigation of a non-CE-marked medical device should at least be considered for certain circumstances, and notification to the MHRA will not be required if the medical device to be used is CE marked for the purpose under investigation. This comes across as less stringent than the MDR, that says that for class III devices and implantable devices safety and performance data, as a general rule, should be sourced from clinical investigations, and that PMCF studies that involve

“submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned”

So, in 2020, should we or should we not follow MHRA guidance when a UK site is involved in our clinical investigation?

As if we did not already have enough challenges in the EU medical device environment, there the CORONAVIRUS (or COVID-19) appeared, originating in China and spreading across the globe by now. By the end of last month, it started affecting device availability at the hospitals, but by now it also has a direct effect on our clinical study work due to travel restrictions and hospitals starting to keep out clinical trial monitors. Making remote monitoring in spite of its down sides, all of a sudden a much more attractive option. But are your EU clinical study sites ready for that, and how does that work again with the GDPR?

In the meantime, let’s not forget the MDR DEADLINE being right around the corner. With a substantially higher demand for qualitative clinical evidence, and, as a brief reminder, reasons for this include that:

• existing clinical evaluations need re-assessment following limitations on equivalence, state of the art, as well as clinical data that are considered suitable,
• several devices have been up-classified, and will require a more solid evidence base than before,
• planned activities for Postmarket Clinical Follow-up will require actual data collection, and are no longer a paper exercise, and
• clinical trial/ investigations supporting the regulatory files need to be conducted in compliance with the MDR and other Good Clinical Practices, such as ISO 14155.

So in short, due to a broader scope, better follow-up, as well as limitations on the use of existing clinical data, ‘the pressure is on’, especially for the clinical evaluations. The problem is, that when you do not have (access to) a lot of clinical data there is nothing to evaluate. I already see issues appearing with lower class devices that have been on the market for ages, but where complaint data and some publications from equivalent devices were considered insufficient under the MDD: Where does that leave us under the MDR?

So, and I cannot emphasize this enough, when in the fortunate situation that your device still has a valid CE mark, please make sure to pro-actively collect clinical data on safety and performance appropriate for your device and its intended purpose now.

The MDR mentions ISO 14155 as the GCP for medical devices, and the 2020 version will be coming out soon. An obvious attempt was made to align the two, but one should pay attention though, since their requirements with respect to clinical investigations are not 1:1. The MDR is, for example, more ‘lenient’ with respect to AE documentation, requiring recording of any AE

“identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation”,

whereas ISO 14155 requires all AEs to be documented. Furthermore, there are some nuances with respect to pre- and postmarket clinical studies. I will write a separate post on this topic soon, but when planning your clinical investigation make sure to know what bucket your medical device clinical trial belongs to, pre- or postmarket, interventional or observational, feasibility or regulatory, and what that means for the applicable rules.

In CONCLUSION, 2020 for sure is an exciting year for those in the medical device clinical trial environment and beyond, with a lot of question marks. Unsure what to do? Stay tuned and feel free reaching out for advice, ACS can help you finding the most cost-effective way for your device through this clinical evidence labyrinth.

Annet

EU MDR DEADLINE MAY 2020: CLINICAL EVIDENCE STATE OF AFFAIRS AT YEAR’S END

With less than 5 months to go until application, the development of guidance on the clinical evidence collection process under the EU MDR is progressing scarily slow.

The updated overview from December suggests we theoretically will get some more clinical guidance the next few days, but I would not bet on it. The 2-year delay in EUDAMED implementation, indeed, seems a valid argument to prioritize some clinical evidence guidances over others serving as input for EUDAMED. However, being in the process of preparing clinical evaluations, as well as pre- and postmarket clinical investigation documents, it would be very helpful to have some of the planned guidances available now, and not 2 minutes to midnight.

Guidance documents issued sofar with interesting clinical aspects include the following:

Guide on the summary of safety and clinical performance (August, MDCG 2019-9), providing instructions regarding the SSCP as applicable for implantables and Class III medical devices. Besides some general elements, the most noteworthy I find is that the summary

• in line with the clinical evaluation, should include favorable and unfavorable data,
• in addition to English should be available in the Member State languages where the device is intended to be sold,
• should be available as a HCP version and a patient version for implantables where patients will be given an implant card, and class III devices intended to be used directly by the patients, and
• should be referenced in the IFU with its location in EUDAMED (interesting given the 2-year delay),

Guidance regarding the ‘person responsible for regulatory compliance’ (June, MDCG 2019-7), mentioning that all manufacturers are required to have at least one person available within their organization responsible for regulatory compliance, and while referencing the MDR for guidance on what the PRRC is expected to do in case of EU clinical investigations and performance studies, it emphasize also that the manufacturer shall ensure that a signed statement by the

“… person responsible for the manufacture of the investigational device [for performance study] that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation …”

Note that per MDR (and ISO 14155 as well, refer to my previous blog post) ‘investigational device’ means any device being assessed for safety and/or performance in a clinical investigation, so this includes devices subject to PostMarket Clinical Follow-up studies.

Guidance on qualification and classification of software (October, MDCG 2019-11), providing direction for software falling within the scope of the MDR, and emphasizing that manufacturers of Medical Device Software (MDSW) must ensure

“that any claims, relating to the intended medical purpose of their MDSW are supported by clinical evidence”,

and that for all MDSW safety and performance is ensured

“… throughout the lifecycle of the software, through a continuous process of clinical and/or performance evaluation and risk management”,

and last, as a kind of Christmas present:

Guidance notes for manufacturers of class I medical devices (December, MDCG 2019-15), providing direction to Class I medical device manufacturers; among other things, emphasizing once more that under the MDR

“All devices, regardless of risk classification, require a clinical evaluation as part of the technical documentation”,

with the note that

“… the level of clinical evidence will be appropriate in view of the characteristics of the device and its intended purpose”.

giving some room for the lower risk class of devices on the degree of clinical evidence needed, provided the manufacturer can justify this in light of device at hand. So not every device requires a Randomized Clinical Trial!

In conclusion, with the MDR deadline around the corner for all the applicable devices (all new medical devices, not upgraded class I devices, and class IIa, IIb, and III devices with significant changes) for clinical activities & documents, we still need to rely on our own interpretation of the applicable sections in the MDR in combination with existing guidance documents for the MDD and the AIMDD. Let’s keep out fingers crossed that for patient’s safety sake, all parties involved have a similar interpretation while working on the collection & evaluation of clinical evidence substantiating safety and performance of the concerning medical devices.

With the Best Wishes for 2020!

Annet