EU MEDICAL DEVICE STUDIES IN 2015: A YEAR OF CONTRAST?

contrast_2015Happy New Year!

Indeed the year 2015 did become an interesting one looking at it from an EU medical device study perspective. Especially since some of the events seem to create areas for tension: More transparency on clinical data, but also better data-protection; further digitalisation of clinical study processes including the Informed Consent, but also standards and policies sticking to the traditional way of working to name some. A list of key events you find below.

Clinical data transparency

On January 1 the new EMA policy on publication of clinical data entered into force: similar to the FDA the agency will publish clinical data supporting marketing authorization of medicinal products for human use. On January 8 the NEJM published the suggested policy for U.S. Clinical Trial Results submission to Clinicaltrials.gov, proposing result reporting of all studies registered on clinicaltrials.gov on the primary and secondary outcomes, and all serious and/ or study product related adverse events regardless their marketing approval status. In April the WHO calls for more transparency on the results from clinical studies to ensure that medical safety and efficacy decisions are evidence based. In September the EMA and the WHO agreed to share non-public information on the quality and efficacy of  medicines on the market or under review in the EU, and beginning December the Dutch Central Committee for human research announces the amendment of the on-line submission system and form to include that clinical study results will be disclosed unless the sponsor has well-founded objections.

Although the above events tend to focus on medicinal products, transparency is also a focal point in the Medical Device Directive overhaul, and one of the key objectives of the Eudamed database is to enhance overall transparency as clearly stated in the latest version of the EU council.

Data privacy

As previously blogged, privacy of study subject information typically is well guarded in clinical studies, but with the globalisation of clinical studies and the level of data protection being different across the globe, and journals requiring sharing for raw clinical data-sets (the BMJ policy on data-sharing took effect in July), data protection has become even more important in clinical studies; In June the EU council approved the proposed data protection regulation. In September the EU’s data protection supervisor Buttarelli stressed that

“today’s trends require a fresh approach”,

and on September 8 the US and EU reached agreement on how to deal with EU-US privacy dataflow. December 15, the EU commission agreed to the new dataprotection regulation, the final texts to be adopted at the beginning of this year. Among other changes, it includes a clarified

“right to be forgotten”,

when you no longer want your data to be processed, and there are no legitimate grounds for retaining it, the data will be deleted.

Electronic Informed Consent

The latter and also other matters related to data privacy are addressed via the patient informed consent, where also interesting trends became visible in 2015. The FDA published their draft guidance for the use of the electronic Informed Consent in March, and, closer to home, in August the NHS approved the use of eConsent technology in a clinical study; comparing eConsent with the traditional paper Informed Consent in the UK. Theoretically the use of an eConsent can help to improve the informed consent process allowing for easier access to information, so this can be a great step forward. As of yet, however, the clinical trial standards such as ISO 14155:2011 and the regional Ethics Committees, such as the Dutch Central Committee for human research, typically require a written informed consent:

“Informed consent shall be obtained in writing from the subject and the process shall be documented before any procedure specific to the clinical investigation ….”,

and pending any amendments it is therefore key to properly document any deviations in that respect. Given the time typically required to adjust standards and guidance’s, this may last a while.

Conclusion

In conclusion, there were many interesting events in 2015, but it will be even more interesting to see how some of the above elements will develop in 2016. I will keep you posted via this blog, so stay tuned and do not hesitate contacting me in case of any questions.

ACS newyear 2015

 

 

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THE ON-SITE MONITOR: A SPECIES NEARING EXTINCTION?

mamouth

Site monitoring represents minimally 15% of your total clinical study budget, and concerns an expense that benefits enormously from digitization and evolving regulatory insights: Electronic data capture and querying, online study training, remote monitoring, and risk-based monitoring, and makes you wonder whether it is still necessary to have on-site monitors?

Source data

The number one reason for the on-site monitor is proper source data verification, i.e. the process to ensure that data are verifiable, correct, and complete. In spite of electronic means, such as EDC and remote desktop sharing, there are certain things you can only verify when on-site. On-site monitors review unselected hospital files in their own way and at their own pace with less security and confidentiality issues, often identifying valuable data a site study coordinator overlooked.

Training

Although internet based training tools are of great help (re-)training a site study team, there is nothing more efficient than a face-to-face training with in person interaction. Whereas on-line trainings can be rushed, there is no escape from a person sitting next to you and providing – hands-on – instructions and asking questions. Especially in medical device studies, where adequate training is key to a successful study outcome (also refer to an earlier blog of mine) and patient safety, the impact of on-site and hands-on training should not be underestimated. In case of an investigational medical device

Relationship

Less tangible, but ever so important is that on-site monitors do more than source data verification and clinical study (re)training  – they achieve much of the improvements in data quality through repeat personal contact. This involves maintaining good relationships with the entire site study team, which includes more than the study coordinator, and is something which nearly impossible to do from a distance and at a fixed point in time. Experienced monitors also develop their own network and useful contacts for future clinical projects.

Principal Investigator

Principle investigators are responsible for the implementation and management of the day-to-day conduct of the clinical study, as well as the data-integrity and the safety of the study patients at his/ her site, and as such needs briefing on a regular basis, especially in case of issues. Because of their busy schedule and priority with patient care, such typically does not work very well by sending a written report or requesting presence during a remote monitoring visit. Regular on-site presence with the flexibility to brief the principal investigator at any moment when there is a – sometimes unforeseen – gap in his/ her calendar works a lot better in this respect.

Human Touch

No matter how cost-effective remote monitoring and querying via EDC may seem, there is no substitute for the human touch in many interactions for the clinical study execution at a site. Knowing that much of communication is non-verbal, it is not surprising that many site study team members prefer dealing with a person face-to-face and in their own language rather than a website, or an overseas data-manager that they have never seen.

Conclusion

Referring to the title of this blog, evolving means and approaches can help to make clinical study monitoring much more cost-effective, but can never replace the on-site monitor as there are too many aspects of this job that need a flexible face-to-face interaction.  Not the least in the area of medical devices with a growing need for high quality clinical evidence and with the upcoming revision of the EU medical device directive in mind. The Mastodont may have gone extinct but the elephant still stands …

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TRANSPARENCY IN MEDICAL DEVICE CLINICAL STUDIES – THE FUTURE IS NOW

transparancyThe era of full clinical data transparency is here, and that includes medical devices: EMA issued their policy on the publication of clinical data effective as of the beginning of this year, and is currently requesting feedback on the application of the transparency rules of the EU clinical trial regulation, addressing medicinal clinical data. Although generally speaking medical device study policies and regulations tend to be behind on the ones for medicine, for sure this will not be the case this time: The FDA/ NIH proposals on publication of clinical study results of studies registered at ClinicalTrials.gov includes medical devices, and – as I previously blogged – the current version of the EU MDR has strong elements on clinical data transparency similar to EMA. Furthermore J&J recently announced that they will make their clinical data of approved devices available to the public.

There are several indisputable reasons as to why it is necessary to strive for full transparency regarding clinical data, not the least being that it allows for clinicians, patients, and policy makers to make well-informed decisions about health care, thereby guarding patient’s safety and well being. Then why is there so much debate regarding this development, and what are factors that need weighing when deciding to go public with clinical data?

 

Data protection

Privacy of study subjects and the confidentiality of their medical data are well guarded in most clinical studies and clinical data are typically only shared in an anonymous way. Incidents, however, are known to happen where personal data gets out into the open, and technologies on data-bases are evolving quickly. The latter making collection of more complex clinical data easier, but also full anonymisation of the data more challenging. In addition, there are situations where certain data, for example on life threatening adverse events, need to be collected and reviewed in a non-anonymous way for an adequate interpretation. On top of that clinical studies are becoming more and more global, and what type of data is considered to be private, and the level of data protection is different across the globe.

Bottom line is that raw clinical study data may contain personal information, and care needs to be taken to ensure that the clinical data that are published for transparency reasons are fully anonymous according to the most stringent criteria. Especially now that many journals require that authors share raw clinical data supporting their manuscript and that reports should include adverse events as is suggested in the FDA/ NIH proposals.

 

Intellectual property

Clinical research, driven by industry as well as university, flourishes on new ideas and inventions, its development, and resulting publications. Although inventions can be patented, intellectual property for medical devices is even harder to protect than for medicines, and the requirement to publish clinical data of any interventional trial regardless the study phase or whether the product under study has been approved, as proposed for studies registered at ClinicalTrials.gov, may well become counterproductive if not addressed well. Such requirement could reduce the willingness to register early phase clinical studies and/ or slow down developmental activities.

 

Clinical data interpretation

Correct interpretation of clinical study data is not an easy thing to do. Complete books are written on this topic, and insight are still evolving: the exact objective of the study, analyses methods, size of the study and size of the study product effect being only a few of the factors that influence interpretation of study data and therefore its conclusion. Even researchers are facing challenges in this respect, so one can only guess what happens when people looking at clinical data or a study report do not have the full picture and/ or expertise to interpret the data the right way. Especially in the early phases of a product development such can be tricky as you may kill a potentially promising therapy when misinterpreting or a misrepresenting the study results. Therefore it will be key that the layman’s summary, as for example required per draft MDR, is concise as well as unambiguous.

 

Conclusion

In conclusion, clinical data transparency is an indisputable requirement that is becoming more and more embedded in policies and regulations including those for medical devices. Since many medical devices clinical studies are registered at ClinicalTrial.gov, clinical study sponsors (industry as well as physicians) need to consider carefully now what and how they want to present their clinical study data to the public, and whether they want to provide feedback on the clinical data transparency proposals that are open for public consultation to ensure proper weighing of the above mentioned factors. Please feel free to contact me at any time in case you want to discuss the above.

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WHAT CLINICAL BENEFIT DO YOU WANT TO PROVE IN YOUR STUDY?

Dilemmas

Defining the clinical benefit or the efficacy parameters for your product in a clinical study is a challenging but critical activity: Do I aim to show the effect of product itself or that of a treatment as a whole, what study parameter/ endpoint best reflects the benefit of my product, and should I assess the effect in a controlled clinical trial environment or in a real world setting? Especially for medical devices in Europe where upon market entry only clinical evidence is needed supporting product safety and performance, a whole range of options and therefore debate is possible and necessary in a postmarket setting. The fact that different stakeholders may have different opinions complicates the discussion even further, physicians told me several times that

”I check my patient to see and hear what (s)he feels and thinks, and that, in combination with test results, is what drives my diagnosis and treatment, not whether some number dropped or rose to a certain level”.

Such being the case for babies with severe eczema not being able to sleep, as well as for patients with end stage cancer, where quality of life generally prevails over other parameters. The problem with parameters such as quality of life, however, being that it can lead to large and long-term clinical studies unless using less conventional methodologies. In addition regulatory bodies or insurance companies may well have an interest in a different more clear cut study endpoints. In this second post in the clinical evidence dilemmas series, you find below some thoughts on 3 aspects that to my opinion need careful consideration when designing your medical device study:

Product effect

A clinical study is generally set-up to show efficacy of the product itself, excluding as much as possible other medical treatments or interventions that may affect the same study endpoints. This, indeed, is the most logical choice when aiming to show product efficacy for regulatory purposes, but this may well differ from how the product is or will be used in daily practise. In the real world, concomitant therapies may interfere and reduce the effect of the product, or in some cases treatments may even strengthen each others effect. Electroporation for example has been shown to destroy cancer cells, but also to enhance local chemotherapy. So here the question is whether in your clinical trial you want to show the effect of a product, or a treatment that includes that product? And again keep in mind the answer may depend on  the stakeholder: a physician aiming to treat his patient the best he can will see this different than regulatory body that wants to know the pure benefit of the product itself.

Patient outcome

So what about the patient? As the above quote already illustrates, daily practice is and should revolve around the patient rather than a medical product, and therefore prefers to see patient reported outcomes/ endpoints such as quality of life. Clinical trials, however, typically are designed to show a maximum effect at the smallest possible sample size and therefore study endpoints in medical device studies are often surrogate ones as these are better to measure. While this increases feasibility of a clinical trial, and therefore also addresses an ethical dilemma, the real world tends to ask for other endpoints than those addressed in a clinical trial.

Another challenge in this respect is that some medical products, such as diagnostic devices, do not treat the patients by itself and a potential effect on patient outcome(s) will only be achieved indirectly. In other words via the professional users who, based on the information provided by the device in combination with other information, decide to apply a certain therapeutic intervention. Such intervention may in turn lead to a certain outcome, and therefore it may be hard to show a product effect on patient outcome in a clinical study.

So what parameter/ endpoint to measure the effect of your product by, and in what setting, is not an easy question to answer. When, however, not choosing patient outcome as a primary study endpoint, at least include one or more as secondary.

Training

For many medical devices, adequate training on its use is key to a successful outcome. Whether it concerns a highly sophisticated surgical instrument like da Vinci robot or a diagnostic tool like a blood pressure monitor, correct handling of the device can have a strong impact on the product safety and efficacy. In clinical trials participating sites and users are well trained for patients safety as well as products outcome sake. With wide spread use, however, the device will be operated by less well trained experts for several reasons, thereby reducing efficacy and sometimes increasing risks for the patients involved. The question is whether and how to include this learning curve (which may be substantial for some surgical devices) in your clinical trial? This would make the outcome more representative for a real-world setting, but also increases the size of your study.

Conclusion

As will be clear from the above, unfortunately, there is not just one answer to the question(s) raised at the beginning of this post. A lot depends on the type of device and what you exactly want to prove and when in the product life cycle. Often, however, it is not a question of either/or, but more a question of how much you can afford to invest in your clinical trial to show product benefit.

Please feel free to contact me to discuss the above, or any other topic at: annet.muetstege@appliedclinicalservices.com.

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EU MEDICAL DEVICE DIRECTIVE REVISION CONTINUED

safetyLast week Glenis Willmott was announced to be the new rapporteur for the Medical Device Directive revision. For me that raised the question what effect this will have on the clinical research aspects of the proposed Medical Device Regulation. Given her interest and activities for the recently revised clinical trial regulation for medicinal products, an easy bet is that the focus will be on clinical trial transparency and patient safety. In the announcement she stressed:

“We must ensure the industry is transparent and works in the interest of patients.”

So what elements were incorporated in the clinical trial regulation under her supervision, and what of that is part of the current version of the MDR and may stay or change?

Public European database
Willmott is a strong advocate for full clinical data transparency through a publicly accessible European database guarded by the EMA. Under the revised clinical trial regulation this database is meant to register all clinical trials in Europe, and should include a lay summary of all trial results uploaded within 1 year after the trial ended.

The concept MDR is also striving for an EU database, to ensure that

“every clinical investigation is registered in a publicly accessible database”,

and the trial sponsor shall

“within one year from the end of the clinical investigation or from its early termination”

submit a summary of the results accompanied by a

“summary presented in terms that are easily understandable to a layperson”

In other words the concept MDR contains wording similar to that in the clinical trial regulation, and we can be pretty sure that this will be implemented, although the exact construction of this Eudamed database is still questionable.

Safety reporting
The clinical trial regulation also aims to simplify safety reporting and allows for suspected unexpected serious adverse reactions to be reported in the EU pharmacovigilance database directly instead of submission to each EU Member State.

The concept of the MDR has a different phrasing in this respect:

“Sponsors should report adverse events occurring during clinical investigations to the Member States concerned”

Since many clinical trials nowadays have an international character, a change of the MDR towards the clinical trial regulation would certainly help making adverse event reporting easier and more consistent, and therefore be development for the good.

Clinical Study Report

Also for the sake of full clinical data transparency, the clinical trial regulation requires that all clinical trials and reports of trials used in a marketing authorization request are to be registered or published, whether the request is approved, rejected or withdrawn.

Again the proposed MDR contains very similar phrasing that

“Irrespective of the outcome of the clinical investigation, … the sponsor shall submit to the Member States concerned a summary of the results of the clinical investigation”.

The difference being that the current version of the MDR, differentiates between the different class of devices as it also says that

“A summary of the safety and performance report should be publicly available via Eudamed” in case of class III medical devices.”

So this also is a keeper in the final MDR, although it may become more stringent than it currently is.

Paediatric Trials
Another field of Willmott’s interest relating to patient safety, concerns the fact that minors are underrepresented in clinical trials. This because the population is relatively small, the trials are complex, and the bureaucratic burden is high. The safety and efficacy profile of a product in an adult, however, cannot simply be translated to a child: A pacemaker has different requirements in size and settings in an adult than a child.
The new clinical trial regulation is anticipated to address these challenges with simpler and more uniform rules facilitating the execution of cross-border trials.

The proposed MDR contains a complete section addressing clinical studies in minors, listing the conditions that have to be met in order for them to be conducted. Indeed, looking for a more uniform approach across the EU borders, but I wonder whether this, especially in combination with the so feared scrutiny procedure, leads to a lessening of the bureaucratic burden and more paediatric trials. Maybe this is a piece in the MDR that will develop for the good under Willmotts supervision.

Conclusion
In conclusion, the effect Willmott’s appointment will have on the development of the MDR is hard to tell at this point in time. However, given her involvement in the clinical trial regulation and interests, we can expect that clinical research will get even more attention than it did under Roth Behrendt’s reign.

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CLINICAL EVIDENCE DILEMMAS: IS MY CLINICAL STUDY POPULATION THE RIGHT ONE?

DilemmasIs my study population the right one, or in other words: Does my clinical study population represent the patients the study product is meant for? An essential question to answer when designing a clinical study to collect clinical evidence regarding product performance. Especially in the area of medical devices, but also food, where the intended population can very broad, such is less straightforward as compared to pharmaceutical studies. And a recent publication illustrates that it is harder than it seems to choose the right clinical study population.

Key factors driving the choice of the study population, as previously summarized in a presentation, are:

Safety

Depending on the amount of existing clinical evidence, the study patient selection criteria will be more or less strict. The less data is available the more the clinical study population will be limited to protect study subject safety, and the further it deviates from the intended population. In pharma such is dealt with via the different premarket phases, but in medical devices this is not the case and typically at market release the available data is minimal. In medical devices one also needs to weight in the class of device: selection criteria for a first in man clinical study for an active implantable device will be more strict than those for a non-invasive monitoring device.

The consequence of the above, is that the clinical study population can differ substantially from the final population the product is used for. In daily practise patient selection criteria will be less strict and factors like co-morbidity and age may well affect safety. Therefore in the end safety will need to be established in daily practise. If not done pre-market, for example because the concerning product is implanted and its mode of action stretches over a period of several years, a thorough postmarket surveillance program is a must. Which is exactly one of the reasons why there is so much attention by the Notified Bodies and the MDD under revision for an adequate postmarket clinical follow-up, following the hip and PIP implant scandals.

Efficacy

In Europe medical device performance often does not include efficacy, although this may very well change once the proposed changes to the MDD are finalised.

When still choosing to collect clinical evidence on efficacy, for example for reimbursement purposes, patient selection criteria are often very strict to reduce variability and maximize product effect at the lowest possible clinical study size. When there is no safety issue, one can choose to widen patient selection criteria and stratify for patient sub-groups and analyse for confounding factors. This, however, will lead to a rise in the study sample size: One only needs to look into the medicinal study sizes to get an idea.

Regardless such efforts, however, it will still be challenging to mimic a broad population of people including all ages and co-morbidities, in a non-study setting with less extensive or other patient diagnostics and device training. Therefore daily practice trials remain necessary to evaluate to what extent it erodes device efficacy.  Keeping in mind the acknowledgment in pharma that there is a gap between efficacy and effectiveness, one may even wonder whether for some medical devices, such as for example monitoring or diagnostic devices, it does not make sense to ‘skip’ efficacy studies and rather start an observational study after market release instead?

Ethics

As mentioned above, widening of the clinical study population leads to a larger sample size, and then the question becomes relevant whether the concerning clinical trial is still feasible in terms of people, time and money. This embeds an ethical concern also: can we start a trial that we may not be able to finish, especially taking into account the fact that the majority of clinical trials take longer than expected? In that light I firmly believe one should always carefully weight what clinical project(s) to spend your resources on: a large efficacy study with a select patient group that will need a follow-up study in a real world setting, or a clinical study showing that the product works in the intended population in daily practise.

Conclusion

In conclusion one can say that it is hard to define a clinical study population that covers all aspects in one clinical study for safety, efficacy, but also for feasibility reasons. Whether such can be done or whether it is more cost-effective to run 2 or more clinical studies needs to be determined on a case by case basis.

Please do not hesitate to contact me in case you want to discuss any of the above or stay tuned with my blog: the next one on this series on clinical evidence dilemmas will follow soon.

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