GENERAL DATA PROTECTION REGULATION – 5 CLINICAL ASPECTS

consentAs mentioned in my previous post on the MEDDEV 2.7/1 revision 4, the second quarter of 2016 is characterized by several big steps from clinical evidence perspective: Besides the publication of the new version of the MEDDEV 2.7/1, consensus was reached on the new Medical Device Regulation (MDR), and in May the General Data Protection Regulation (GDPR) entered into force.

Since data protection and the informed consent for clinical studies are inseparable, in this post I want to share my thoughts on some key elements from clinical study perspective:

Health Care Data

Clinical studies concern any systematic collection of health data, and the definition of health data under the new GDPR is very broad, including

“all data pertaining to the health status of a data subject which reveal information relating to the past, current or future physical or mental health status of the data subject”.

Under the new GDPR such health data are subject to strict requirements: It prohibits processing of data concerning health, unless subject has given explicit consent to the processing of those personal data for one or more specified purposes.

This is particularly of note since this implies that informed consent is also applicable for registries or other non-interventional studies, whether these are prospective or retrospective. Therefore a substantial impact on epidemiologic studies can be expected where collection of informed consent can be very challenging due to scale for example.

Anonymization

In principle data collected within the context of clinical studies are anonymized before they are being processed. As addressed in another blog on transparency, however, the challenge with current technologies, especially when medical devices are involved, is that personal identifiers are often embedded within the diagnostic tools or the investigational devices (think images, ECG strips, …) to facilitate processing. Also the GDPR definition of what should be considered identifiable is very broad, and not just looking at a name or date of birth:

“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 besides we are collecting health data, this makes an informed consent an in-disputable part of any clinical studies, interventional or not, and even more so when medical devices are involved.

When in addition the study will be monitored and/ or there is a likelihood that non health care professionals will be reviewing the study patient hospital files, this needs to be mentioned in the patient information and the data-subject will need to consent to this.

Informed Consent

The informed consent process is not an easy part of clinical studies, and the GDPR indicates consent needs be specific and unambiguous, i.e. the

“Consent should cover all processing activities carried out for the same purpose or purposes. When the processing has multiple purposes, consent should be given for all of them”,

meaning for example that when blood or tissue samples are collected and stored for possible future use, subject’s consent is required for this, and research such as with Henrietta Lacks’ cervical cancer cells is a no-go.

The typical cut-off age for giving consent in clinical studies is 18 years, and I find it interesting to see that the GDPR indicates a child can give consent to the processing of his or her personal data at the age of 16, and below that

“such processing shall be lawful only if and to the extent that consent is given or authorised by the holder of parental responsibility over the child.”,

implying that – at least for observational studies – the age for giving consent could be lowered.

Also of note is that the GDPR refers to the Clinical Trial Regulation for medicinal products for the consenting to participation in research activities. Where does that leave us with medical device studies? Should we follow the Clinical Trial Regulation, or is it OK if we follow ISO 14155 – GCP? Since provisions with respect to the informed consent process are very much alike, I do not expect any issues, but still…

Consent withdrawal

Any study participant has the right to withdraw consent at any time without any explanation or any consequences, and the GDPR once more emphasizes this. Of note in this respect I find, that in the clause on the right to be forgotten (article 7), it says that erasure of data does not apply when processing of data is necessary for

“ … scientific or historical research purposes or statistical purposes in accordance with Article 89(1) in so far as the right referred to in paragraph 1 is likely to render impossible or seriously impair the achievement of the objectives of that processing; …”

In other words, in case a study participant withdraws consent, processing of anonymous data collected until that point in time is still possible if such is needed for the objective of the clinical study.

Data-processing outside of the EU

With the globalization of clinical studies in mind, it is of note that the GDPR is very comprehensive on transfer of personal data outside of the EU, since third countries are likely to have less strict regulations around data-protection. Aspects to consider in this respect are the location of the study sponsor and the database, but also of possible core-labs. When, for example, clinical study images of EU subjects are sent to a core-lab outside of the EU for screening purposes, the subject should be informed and consent to this specific aspect of the study before such is done.

Conclusion

In conclusion, generally speaking I do not expect many changes for clinical studies under the new GDPR. Most of the elements addressed above typically are already taken into account in the clinical study informed consent. The main challenge will be for retrospective and epidemiological studies: to obtain subject’s consent or ensure fully anonymous data processing.

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GLOBALIZATION of MEDICAL DEVICE TRIALS: MUTUAL RECOGNITION of CLINICAL STUDY RESULTS

globeI am looking forward to the International Congress on Clinical Trials for Medical Devices in Berlin later this month, where I will be talking about the globalization of clinical trials and mutual acceptance of foreign clinical data for regulatory and guideline purposes.

An abstract concerning my presentation you can find on the website of CTMD 2016. In short, I am intrigued to see that while advancing technologies, and international guidelines facilitate the extrapolation of clinical data from one region to the other, the changes with respect to acceptance of foreign data seem to be minimal. Especially in the US where > 60% of the safety and effectiveness data for PMA’s originates from US soil only over the last 15 years.

It seems that the benefits are outweighed by other factors, such as intrinsic and extrinsic ethnic differences. As these might well be hard to overcome, I wonder whether, in medical devices, we should introduce the concept of bridging studies similar to what is done for medicinal products. I am looking forward to the discussions, and please do not hesitate to contact me at Applied Clinical Services.com when looking for support for your medical device study.

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MEDDEV 2.7/1 REVISION 4: A HIGHER DEMAND FOR CLINICAL EVIDENCE

hamp-guidelinesIn Europe the second quarter of 2016 is characterized by several big steps from clinical perspective: In April the General Data Protection Regulation (GDPR) entered into force, in June consensus was reached on the new Medical Device Regulation (MDR), and also in June, the MEDDEV 2.7/1 revision 4 was published. Although the latter concerns a medical device guideline and is not legally binding, I am sure it will impact the clinical evidence needs for medical devices in Europe. In this post I wanted to share a couple of aspects that struck my attention on the new version of the MEDDEV:

MDR

Reading the new version of the MEDDEV, I cannot get away from the impression it anticipates the new MDR: For example the conformity assessment with requirement on  performance (Appendix A7.3) describes 1:1 the MDR definition of clinical performance:

“the ability of a device to achieve its intended purpose as claimed by the manufacturer, including any direct or indirect medical effects on humans as well as the clinical benefit on patients resulting from the technical or functional, including diagnostic characteristics of a device, when used as intended by the manufacturer”.

Similarly the instructions to update the clinical evaluation throughout the product life cycle with clinical data along with its frequency (see below), is as described in the MDR. So to me it seems the new MEDDEV more or less enforces compliance with a regulation yet to be.

Clinical Evaluation scope

The requirements on content of the clinical evaluation report concerning claims on safety, performance, and risk/ benefit weighing seem comparable to the previous version, but the scope of the clinical evaluation has broadened. The clinical evaluation, for example, should start during the product development phase, and in addition to the clinical data should include review of all information materials. Where information material

“refers to the labelling, instructions for use and the manufacturer’s promotional materials for the device under evaluation”,

so goes beyond the IFU and product labelling, and includes marketing materials.

Product Life Cycle

The clinical evaluation is also much more an ongoing process throughout the full product life cycle, beginning at the start of the product development and continuing after CE mark. The revision 4 includes an indication as to when the clinical evaluation report should be actively updated: at least annually in case of high risk devices, and every 2-5 years in case the device does not carry significant risk.

Post Market Clinical Follow Up (PMCF)

Post Market Surveillance (PMS) has become much more a fixed part of the clinical evaluation. For CE-marking the purpose as specified in revision 4 is two-fold:

“document that there is sufficient clinical evidence to demonstrate conformity”,

and

“identify aspects that need to be addressed systematically during post-market surveillance”,

and one of the tasks of the clinical evaluator is to determine the needs for PMCF.  Besides any residual risks, (s)he should also take into account any uncertainties or unanswered questions, such as for example on long-term performance and wide-spread use, to assess the needs for PMCF studies. Especially in case of implantable devices, I am pretty sure this will lead to more post-market studies as it will be challenging to address all of that in pre-market studies, a topic I will address in my next post on clinical evidence dilemmas.

Clinical Investigation requirements

The revised MEDDEV is rather explicit as to when clinical investigations are needed and what clinical data should look like to support safety:

“For compliance with Annex X section 1.1.a MDD and Annex 7 AIMDD, clinical investigations with the device under evaluation are required for implantable and class III devices unless it can be duly justified to rely on existing clinical data alone.”,

and

“the clinical data should contain an adequate number of observations (e.g. from clinical investigations or PMS) to guarantee the scientific validity of the conclusions relating to undesirable side-effects and the performance of the device”.

With respect to safety the new  MEDDEV even includes a table with sample size thresholds as to what would be considered an adequate sample size depending on the estimated probability of observing an undesirable event. In other words, the new MEDDEV 2.7.1 will demand more and larger clinical studies to substantiate safety and performance.

Conclusion

In anticipation of the new MDR, the tasks of the clinical evaluator have been extended, and the demands with respect to clinical evidence tightened under the new MEDDEV 2.7/1. With more attention to detail including the total product package, the full product life cycle, and higher demands for pre- and post-market clinical studies.

Obviously there is more to be said about the revised MEDDEV than addressed in this blog: For example what to think about the qualifications of the evaluator, and the requirements for a device to be assumed equivalent? Feel free to contact me in case you want to discuss, you will find my contact information in the upper right corner of my blog.

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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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