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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Clinical evidence under the EU Medical Device Regulation: More firework on the way.

fireworkThe EU Medical Device Regulation (MDR) and the In Vitro Diagnostic device Regulation (IVDR) entered into force, local governments published guidance how to deal with the new medical device regulations, there is debate on the implementation of the MEDDEV 2.7/1 Rev. 4, and yet the number of posts from my end in 2017 have been minimal. I am afraid this is only symptomatic of what is happening in the clinical environment of medical devices in Europe: the demand for qualitative and manufacturer owned clinical evidence is rising, and medical device companies have only 2 years left to perform a gap analyses AND to address any gaps in their clinical data.

A snap shot of some key events from clinical perspective in 2017:

April 5, 2017 the EU adopts the new MDR and IVDR taking effect 2020 and 2022 for the MDR and IVDR respectively,

May 5, 2017 the final versions of the MDR and IVDR are published,

May 2017: UL publishes a white paper on medical device clinical investigations and ISO 14155,

May 25, 2017, the MDR comes into force

June 2017, EMA announces delay of the application of the clinical trial regulation until 2019 due to challenges with the EU portal.

August 2017, TUV SUD announces extension of the implementation timeline of MEDDEV 2.7/1 Rev 4.

Throughout 2017: several posts on the impact of the GDPR taking effect in May 2018, one includes a comparative table EU vs US you can find here,

December 12, 2017: Dutch Health Ministry and Health Inspection publish guidance on key changes for medical devices,

December 18, 2017, MHRA updates guidance on EU regulations for medical devices and in vitro diagnostic devices.

In short, one can only conclude that 2017 has been an exciting year for medical devices reflecting an environment of change with more firework to come, especially when looking at it from clinical evidence perspective: Changes that concentrate around a more thorough (premarket) clinical evaluation (refering to my previous blog post on that topic) with a more solid clinical evidence base, and a better, stricter postmarket surveillance program that includes Postmarket Clinical Follow-up studies. Medical devices companies better prepare themselves, and if not started at this point in time, perform a clinical evidence gap analysis and start collecting their own clinical data where needed NOW!

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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DUTCH HEALTH INSPECTION – THE 4 KNOWS OF THE CONFERENCE ON CLINICAL TRIALS WITH MEDICAL DEVICES

igz-conf-medical-devicesThe Dutch Health Inspection (IGZ) organized an invitational conference on clinical research with medical devices end of last year. Representatives of the different stakeholders, such as manufacturers, competent authorities, Ethics Committee’s, and health care providers were present during this conference and discussed the current system on this type of clinical studies. The summary and presentations that have been published on the IGZ’s website (see above link) are interesting to read, especially on the following items:

EU guidance and regulations

In his presentation regarding the regulatory environment on medical device clinical research, the Health Ministry representative, Van der Kroef, once more underlined that with version 4 of the MEDDEV 2.7/1 and the upcoming MDR (final text MDR just came out!), more clinical studies and more clinical expertise will be needed (also refer to an earlier post). The Health Ministry therefore calls for better alignment and cooperation between the different stakeholders.

Off-label use

Roles and responsibilities were discussed, and the IGZ emphasized that although by law the manufacturer/ sponsor has the ultimate responsibility, also other parties such as the investigators have theirs (be aware that the latter is also amended in the new version of ICH E6). Specifically off-label use was addressed in this context: Research physicians shall NOT apply a non-CE marked device which is not delivered according to the law, but manufacturers are hesitant to allow for studies outside of intended use. Following the FMS guidance could be a solution to guarantee a safe application of medical devices applied outside of their indication when devices are developed within a health care unit.

Patient Information Letter

consentConcern was expressed with respect to the patient information letter that informs the candidate study participant on the ins and outs of a clinical study. Requirements seem to differ for different rules and regulations, and are complicating its development. Web-based tools are considered helpful for the structure and completeness of the content, but, again, the manufacturer has the ultimate responsibility to ensure that the patient information is brief and clearly written (refer to my previous post on tips & tricks).

Observational Postmarket Studies

Thoughts were expressed that the new regulation will also impact the way clinical studies are submitted and reviewed, and options for a “WMO-light” have been discussed: review by an acknowledged Ethics Committee of studies that do not fall under the scope of the Medical Research Involving Human Subjects Act (WMO). The latter would include any Postmarket observational studies such as registries, so I think this is an important development to keep track of.

Conclusion

The Dutch Health Inspection together with the Health Ministry and CCMO will explore what elements of the discussed topics can be addressed, and are aiming for follow-up in the first half of 2017. I will follow the developments with interest and keep you posted. Stay tuned.

Do not hesitate contacting me to discuss the above or when looking for support for your medical device clinical studies. You can find my details in the upper right corner, click here to send me an e-mail.

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INFORMED CONSENT – 5 CRITICAL ELEMENTS TO MONITOR

consent

Ensuring proper informed consent in clinical studies is a critical process, that protects the rights, safety, and welfare of human subjects involved. It will require even more attention under the new GDPR and with the globalization of clinical trials. Although most involved are aware of its relevance, yet there is hardly a process where I see the same issues over and over again during monitoring visits and audits. The annual GCP Inspectors Report indicates that ICF findings were 5th on the list in 2015. This post addresses the 5 most common findings as well as options for preventive measures:

Language

The purpose of the informed consent process is to inform the candidate study participant on what it means to participate in clinical research and the concerning study in particular: what are the risks and possible benefits, what are you supposed to do and not to do as a participant, and what it is you can expect with respect to your health. All of this should be done in language understandable to the subject (or authorized representative) and in as few pages as possible, to ensure that the candidate study participant can make an informed decision.

Yet, I often come across patient information letters containing complex medical and scientific texts, clumsily translated from an English master, and sometimes even in a language different from the subjects own. To simplify the information letter provided to candidate study participants, local (hospital) information brochures on the concerning medical procedure and/ or disease can be of great help, as well as asking team members to read and provide feedback on the information letter, and using the readability statistics tool in word. And last but not least, ensure to have the information letter and consent available in all applicable local languages.

Content

With the requirement to keep the information as understandable and lean as possible, it is easy to forget to address some of the required elements. What I often find missing, for example, is a reference to the (potential for) personal data being transferred to a country outside of the EU: Under the current EU data-protection regulations, and even more so the new GDPR, the definition of what is considered personal data is very broad and also concerns pseudo-anonymous health data, and one needs to be careful sending such data to third countries with different (typically less stringent) laws in that respect (also refer to my previous post on this topic). Third countries, by the way, include the US, and one should pay attention now that the Privacy Shield is at risk.

globe

Of note in this respect is also, that even though an Ethics Committee has approved an Informed Consent with missing elements, this does not mean you are compliant with the EU data-protection regulations: ISO 14155-GCP clearly states that:

“If national or regional EC requirements are less strict than the requirements of this International Standard, the sponsor shall apply the requirements of this International Standard”, and the standard requires you comply with …”

Tools that can help to ensure your information letter and consent form contain all locally required elements are templates and checklists provided by the local Ethics Committees, as well as your own checklists that you build with time.

Study participant sign off

Good clinical practices are very clear with respect to the fact that the informed consent needs to be signed and dated by the subject him/ herself. ISO 14155 states that:

“… the informed consent shall … include personally dated signatures of the subject and the principal investigator or an authorized designee responsible for conducting the informed consent process”

Still, I find it happening over and over again that a consenting physician or study nurse dates the consent in an attempt to help the subject. Despite good intentions, this really is a ‘NO GO’. The sign off namely indicates that the subject was personally and timely involved, i.e. before the start of the study or data-collection, and therefore needs to be done by themselves. Besides emphasizing this during the site initiation, the most creative preventive measure I have seen so far is an embedded “stamp” on the consent page that says

“the patient needs to sign and date him/ herself”.

Children

Less than 1/3 of treatments are studied in children, which is a big issue for the applicability of medical products. One of the reasons is that research with minors is only allowed when it meets specific requirements, which includes the informed consent process. In general (the regulations differ per EU country) the informed consent needs to be signed and dated by both parents or their legal guardian when the child is below a certain age, and by both parents or their legal guardian and the child when (s)he is considered capable to understand the informed consent process until the age of 18.  When the child becomes an adult (typically 18) in the course of the study, in The Netherlands (s)he needs to (re)sign the (adult) consent. Requirements in The Netherlands are expected to be broaden in this respect per March 2017, such that re-consent is not required anymore and the transition age becomes 16 years conform the new GDPR.

20170205_191557_resized

With the need for more signatures, unfortunately the chances for mistakes multiply, and I have seen several partially signed informed consents. Also the re-signing when becoming an adult is something that is easily forgotten, so I am happy to see the broadening of the Dutch regulations in this respect. Nevertheless such mistakes are best prevented, and it is key to know the local requirements when running a clinical study with minors, to ensure adequate training of the site study team during the initiation in this respect, and to install alerts in your EDC system to warn you ahead of time when a subject becomes of age.

Version

Every-one involved in clinical studies is aware that the (latest) EC/ IRB approved version of the informed consent should be used. In spite of that, even the best study sites make the mistake to use an old or wrong version. Often because the consenting physician did not have the correct version available after an amendment, or because (s)he did not realize there were different languages available.

The only way to prevent this from happening is to ensure that all involved in informed consent process only have access to the latest, correct version, and that all are aware (by emphasizing this during the initiation) that multiple languages are available should this be expected.

Conclusion

With the above it certainly feels like I am stating the obvious, but apparently there is still room for improvement in the informed consent process. Too bad, since there are plenty of tools and options around to ensure that this key process in clinical studies is handled the right way, and prevention is much, much better than cure; Especially since corrections tend to lead to new mistakes.

Should a correction be necessary then, as a rule of thumb, follow good documentation practices and ensure that for transparency reasons any change, addition, or correction is dated, signed, and explained by the person doing so (could be the study participant!), and involve the concerning Ethics Committee in this process.

Please feel free to reach out in case you want to discuss any of the above or are looking for a monitor or auditor.

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