THE EU MEDICAL DEVICE CLINICAL ENVIRONMENT: UNCERTAIN TIMES

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

Brexit

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.

Annet

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A NEW VERSION OF ISO 14155: WHAT TO EXPECT?

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.

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, 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.

pre_postmarket

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.

Conclusion

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.

Annet

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MEDICAL DEVICE CLINICAL EVIDENCE HIGHLIGHTS 2018/ 2019: ROARING TIMES IN EUROPE

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.

Annet

Happy New Year!

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THE MEDICAL DEVICE CLINICAL TRIAL ENVIRONMENT IN EUROPE

One of the topics discussed during the Medical Device Clinical Trial Seminar in Taipei, was the current medical device clinical trial environment in Europe and how that is evolving. A short version of my presentation, you can find on SlideShare using the following link:

In brief, there are a few key aspects that need to be taken into account when involved in the development and execution of clinical studies with medical devices in Europe, and starting with some of the

Definitions

What is new in Rev 4 of MEDDEV 2.7/1 are the definitions of clinical data, and especially clinical use, i.e. meaning use of a medical device in a living human subject, including devices without direct contact with a patient. In other words this includes a machine that ensures a continuous fluid flow rate to help raising the temperature of a body cavity.

Also new is the clarification of what is sufficient clinical evidence, i.e. data that are adequate in amount as well as quality: During a clinical evaluation the evaluator needs to take into account sample size as well as the type of trials and the regulations that were followed when the data were collected.

The state of the art is also a newly introduced term, and is relevant when evaluating or designing (a) clinical stud(y)ies as that will tell you what therapy to compare the new treatment with.

Further key definitions concern the ISO 14155 definition of a clinical investigation:

any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device

which to me means that any trial on safety or performance is included regardless whether it is pre or post-market. The difference being that a pre-market study is a study conducted with non-CE marked devices, or CE marked devices used outside the intended use, and a post-market study a study after CE mark and with the device used according to the IFU, and a PMCF study a post-market study looking to answer specific questions on safety or performance.

Clinical evidence gaps

Under Rev 4 of the MEDDEV 2.7/1 there are 2 scenarios where the clinical evaluation may indicate you have a gap in your clinical evidence and a clinical study is needed:

  1. When there is insufficient qualitative data to verify that the device meets ER’s 1,3,and 6, and you need a classic Clinical Investigation, or
  2. when there are unanswered questions regarding safety and performance, for example on long-term performance, and you need a Post Market Clinical Follow-Up Study.

MEDDEV 2.7/1 Rev 4 indicates a pre-market Clinical Investigation is needed when your data are insufficient in quantity (it even has a table with an indication on required numbers for safety) and/ or the data have not been collected in a methodological and scientifically sound manner and/ or in compliance with standards, such as ISO 14155, and it is stressed that incompliant studies should not be used for demonstration of safety and/ or performance of the device. Typically a pre-market study is indicated to be required for implantable and high risk devices, but also for new technologies AND class I and II devices with clinical evidence gaps.

MEDDEV 2.12-2 specifies that a PMCF study generally is required for high risk devices and in case of rare diseases (for the latter the amount of clinical data is often low), but also when patient follow-up in the pre-market study/ ies is not in line with the expected product life time, think implantables such as vaginal meshes for example, or when the CE mark was based on equivalence.

EU Clinical Study Regulatory environment

As mentioned also in previous posts, the regulatory environment for clinical studies in Europe is complex and changing. Some of the directives have already been mentioned above, but at a European level we are currently dealing with MDD, the Declaration of Helsinki, ISO 14155, the different MEDDEV’s, and the different local regulations. The variations in the latter, especially for post-market studies, can make it hard to ensure international studies are run in compliance with the applicable regulations.

Higher standardsThe upcoming MDR will make a difference in that respect, as that concerns a regulation to be implemented 1:1 in the local law, it pays much more attention to clinical investigations (count of the word investigation shows a 5-fold increase!), and it requires basically all clinical studies to follow ISO 14155. And mind you, the MDR specifies that also clinical studies not performed as part of the clinical evaluation shall comply with the general basics of good clinical practice’s, so not just the pre-market and post-market clinical investigations.

Study document requirements

So what is generally speaking needed when you are planning to do a clinical study?

Although different in the details and depending on whether it concerns a pre-market of post-market, interventional or observational study, the basics are always the same.

One always needs a protocol, an Informed Consent (also for registries!), regulatory approvals (EC and CA as applicable), a final report, and AE reporting.

Differences between pre- and post-market studies can include for example the need for an Investigator’s Brochure or an IFU, SAE or U(S)ADE expedited reporting, and the need for a study or a liability insurance for a pre-market study or a post-market observational study respectively. From experience I know, however, that the variations are disappearing, and Ethics Committee’s more and more have similar requirements for a pre- and post-market studies regardless whether the latter are observational or not.

Study endpoints and design

Due to variations in medical devices, their intended use, mode of action, and users, designing the right medical device clinical study requires a tailor-made approach for each product:

safety helmetMeasuring safety or undesirable side effects, concerns a relatively clear endpoint as that is all about the collection of Adverse Events, the type, number, severity, and duration. The main item that typically leads to discussion, concerns the sample size; In other words what defines safe, or to what degree are certain device related events acceptable? The table in MEDDEV 2.7/1 provides some guidance in that respect, but typically the focus is to try and capture the serious device related adverse events, so those that relate to the use of the device and led to an injury that is life-threatening, resulted in permanent damage to the body, or required an intervention to prevent this from happening.

The performance endpoint varies a lot with the device involved. Key is that the device must achieve the performances as intended or claimed by the manufacturer, which translates to different study endpoints for a pacemaker, hyperthermic perfusion system, and a dialyzer: The data on the pacemaker for example may have to show that it adequately monitors the heart rate and effectively stimulates the heart when needed, whereas the data of the hyperthermic perfusion system may only need to show that it regulates the rinsing fluid temperature within certain margins.

The effect on the patient also being more clear for one treatment than the other, because performance is not always the same as efficacy: This is where the patient benefit comes into the picture since

benefits are about a positive impact on clinical outcomes, such as a reduced probability of mortality, morbidity, and enhanced Quality of Life, and if anything is claimed by the manufacturer in this respect, clinical data is needed to substantiate the claim.

And then there is the device effect duration to consider: how long do you need to follow a patient before deciding the device is performing as intended? The last in my blog post series regarding clinical evidence dilemma’s will also address this, but the hyperthermic perfusion system and the dialyses can focus on sessions ranging from 2-4 hours, whereas a pacemaker is supposed to perform for 8-10 years! By the time you have collected the clinical data on the pacemaker, the device(model) will be outdated, so typically you extrapolate data or use long-term data from comparable products, and under the current MEDDEV 2.7/1 you will need to do a PMCF study to confirm long-term safety and performance.

Due to the variety in medical devices, the above examples only give an indication of the elements that need to be considered when developing a medical device study and the challenges that come with it, and then I have not addressed design aspects like when you need a RCT or when a single arm study might suffice.

Study design

Aspects for consideration when determining the study design include:

Gaps: Is there a gap in your clinical evidence and what is that? Do you need a study comparing your devices performance versus the State of the Art, then a RCT will be needed, a study confirming long-term device performance can be set-up as a single arm observational study.

Standards: before designing a clinical study, one should verify whether there are any other than the general standards you need to comply with and whether that dictates a certain design. In case of IOL’s for example there is the ISO 11979 that describes pretty much when to do, what type of clinical study, including the sample size.

Scope: Are you planning to use the data for device registration elsewhere? The FDA for example indicates to accept OUS clinical data for medical device applications, but is looking for effectiveness data rather than performance. So in case you are considering using the data collected in Europe to support your product approval in the US, you better take that into account.

Conclusion

Summarizing, in Europe there is a clear trend towards higher clinical evidence demands: Clinical definitions are more comprehensive, clinical evaluations require more and better substantiation throughout the medical device life cycle, and the regulatory environment is becoming more strict including any type of clinical study. Since clinical trials are an expensive, time absorbing, but also a responsible activity, their planning, development, and execution should be done with even more care than before.

 

Please feel free reaching out in case you want to discuss the above or need any support for your medical device study.

Annet

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CLINICAL EVALUATIONS & CLINICAL TRIALS IN THE EU – TAIPEI

Higher standardsI am very much looking forward to the Medical Device Clinical Trial Regulations and Practice Seminar in Taipei September 5th, where I will be speaking on the current EU standards regarding Clinical Evaluations and Clinical Trials as well as the mutual acceptance of foreign clinical data.

The European Regulatory environment regarding clinical evaluations and clinical investigations shows a clear trend towards higher standards of evidence for medical devices with Revision 4 of the MEDDEV 2.7/1 and the upcoming MDR. ISO 14155 or any equivalent GCP is becoming the standard for any clinical study, Pre- as well as Post-market, when planning on using the collected data for support of device safety or performance. More-over, the clinical evaluation has become an ongoing process throughout the full product life cycle, will require manufacturer owned data, and will be needed for all medical device classes. This is very much in line with the developments in the mutual acceptance of foreign clinical data as I previously blogged about, and we see recent publications of guidelines in that respect from the FDA as well as the CFDA.

Do not hesitate reaching out to me in case of any questions or support needed in the collection of clinical evidence for your medical device.

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GDPR: DOES IT IMPACT YOUR CLINICAL STUDY?

consentIt is hard to miss, but as of May 25, 2018, the GDPR becomes effective. Although collection and review of personal data and clinical studies have gone hand-in-hand for decades and therefore I do not expect major changes, the devil tends to be in the details, and I wanted to re-emphasize some key aspect in this post.

Scope

The definition of what is considered private data will be even wider than before under the and includes information where a person can be identified indirectly:

“’personal data’ means any information relating to an identified or identifiable natural person (‘data subject’); an identifiable natural person is one who can be identified, directly or indirectly, in particular by reference to an identifier such as a name, an identification number, location data, an online identifier or to one or more factors specific to the physical, physiological, genetic, mental, economic, cultural or social identity of that natural person”

So when dealing with health care data (which is what we do in clinical studies) even when data is (pseudo-) anonymized and there is no monitoring involved (hardly true nowadays) an Informed Consent is required. This for any type of clinical study including (borderline) observational studies, and I can’t help but wonder where that leaves us for retrospective data-analyses (also see my previous post on the GDPR)?

The GDPR concerns data of all EU citizens, meaning that any ‘party’ collecting or globeprocessing (clinical study) data from an EU person is subject to it, also when they are based outside of the EU. In such cases it is essential that the Subject Information Letter/ Informed Consent contains clear wording regarding transfer of study data to third countries or international organizations that may have different/ less strict data-protection regulations. Mind you, that when the BREXIT becomes effective this likely includes UK-based companies.

Informed Consent

Ensuring proper Informed Consent is a standard widely acknowledged key process when running clinical studies, so most of the responsibilities defined by the GDPR are not new for those involved in it. It is worth mentioning though that the conditions have been strengthened, and most notable that besides being adequate, data collected need to be relevant and limited, and the purpose of data collection should be explicit at the time of data collection:

“The personal data should be adequate, relevant and limited to what is necessary for the purposes for which they are processed”, and

“… the specific purposes for which personal data are processed should be explicit and legitimate and determined at the time of the collection of the personal data.”.

So when a volunteer or patient signs the informed consent, it should be clear what data is being collected, for what purpose, and for how long it will be stored: Study sponsors and CRO’s must make sure they are only processing and storing the minimum amount of data required for the purpose consented to, and special attention is required for any purpose beyond the clinical trial such as use of collected data for training or future research (hardly explicit I think).

This implies that existing subject information letters and consent models require review and modification where needed for any clinical study moving forward to ensure compliance with the GDPR.

The question is whether participants of clinical studies that started before May 25 2018, need re-consenting? The current thinking seems to be that such is not required, but you may want to review your Informed Consent Forms for aspects as mentioned above, specifically data usage beyond the clinical study itself (training, any future research, …) and duration of data storage.

Roles and responsibilities

The GDPR is more specific regarding data controllers and processors and their responsibilities:

“‘controller’ means the natural or legal person, public authority, agency or other body which, alone or jointly with others, determines the purposes and means of the processing of personal data; where the purposes and means of such processing are determined by Union or Member State law, the controller or the specific criteria for its nomination may be provided for by Union or Member State law”, and

“‘processor’ means a natural or legal person, public authority, agency or other body which processes personal data on behalf of the controller”.

In other words, study sponsors (controllers), CRO’s, EDC providers, and Core Labs (processors) involved in clinical studies have their responsibilities spelled out in the GDPR. All should be aware of its content and possible implications, which means ensuring proper Informed Consent and tracking of the use and storage of the collected data throughout the clinical study accordingly.

Physician researchGenerally speaking responsibilities between the different ‘parties’ will be clear, but notably the GDPR includes a section regarding “joint controllers” (Article 26), so I think it is even more important that all parties involved, and  mind you that includes freelancers, clearly define (and document) their roles for the clinical study at hand.

Of note in this respect is also that the study sponsor can also be an investigator: Investigator sponsored clinical studies are no exception nowadays and responsibilities are often blurred for such studies as mentioned in my earlier post on that topic. Therefore I think it is of essence that any investigator is aware of the implications the GDPR when running a clinical study where data is collected from EU citizens and (s)he has both the responsibilities of the sponsor and the investigator.

Conclusion

In conclusion, when dealing with clinical studies the impact of the GDPR is probably limited since we have been implementing the Informed Consent process for decades, but you need to take into consideration 1. a wider scope that includes any type of clinical data-collection, 2. an Informed Consent that needs to be even more explicit, with special attention for data-use beyond the study at hand, and 3. a better specification of the responsibilities of the study sponsor and data processors involved as the consequences in case of a personal data breach can be huge.

Please feel free to contact me in case you are interested in a more in depth discussion regarding the above or in case you are looking for any support with your medical device study.

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