The time in which the European Medicines Agency did not care about medical devices is over.

EMA has published the first of a series of guidance documents to help applicants prepare for obligations stemming from the new EU regulations on medical devices.

The new regulations introduce new roles and responsibilities for EMA and national competent authorities (NCAs) in relation to certain types of medical devices and IVDs. The Agency is working closely with the EU regulatory network and with stakeholders from the pharmaceutical and medical device industries, including notified bodies, to ensure a smooth transition to the new regulatory framework.

The biggest challenge is currently “to ensure we have the appropriate expertise and resources to adequately carry out these new tasks,” said Guido Rasi, Executive Director of Agency.

This first document developed jointly by EMA and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) in close collaboration with the European Commission, focuses on the  stipulation that marketing authorisation applications for medicines with an integral medical device must include the results of the device’s assessment of conformity by a notified body. Approximately 25% centrally authorized medicines include a medical device component, and the majority of these involve an integral device.

EMA will publish further updates to the Q&A document addressing other requirements for various categories of devices, including those made of substances that are systemically absorbed, products which are not clearly defined as medicinal products, known as ‘borderline products’, and in vitro diagnostic tests used to determine patients’ eligibility for a specific medical treatment.

The complexity of regulations correlates with the complexity of products we develop nowadays. The increasing influence of the EMA in the medical device world is a logical consequence. Medical Device manufacturers should learn to understand their notified bodies as well as the EMA better, because EMA is watching them!

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Since 06 December 2018 the guideline on the content, management and archiving of the TMF is final and will be effective from 06 May 2019 onwards. All enthusiasts of paper TMFs should review the guideline carefully and honestly question their way of approaching TMF management over the last 20 years.  Sponsors of multinational studies should consider the following requirements:

  • The sponsor may choose to outsource duties and functions of the sponsor to a CRO. The sponsor remains responsible for the trial and will need to maintain oversight. Therefore, access to the CRO maintained part of the sponsor TMF or at least regular access to relevant documents from it will be necessary to fulfil these responsibilities effectively.
    Do you spend the manpower, time and money to visit your CRO and their local facilities on a regular basis to maintain TMF oversight?
  • The timelines for submission and filing of all documents to the TMF in procedural documents or TMF plans should be defined. This is particularly important for more complex TMF arrangements with multiple parties involved.
    Where timelines are defined, timelines need to be controlled. Do you control the TMF management timelines in your TMF?
  • The TMF should be managed securely at all times to ensure completeness and to prevent accidental or premature loss, unauthorized alteration or destruction of documents. Access to the TMF should be based on a role and permission description that is defined by the sponsor and/or investigator/institution.
    Do you know every storage location of the essential documents throughout the course of your studies? Have you visited the home offices of freelancers and homebased staff? Do you control whether the role-based permissions of accessing the TMF are kept?
  • As per Article 58 of the Clinical Trials Regulation (EU) No 536/2014 “unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical TMF for at least 25 years after the end of the clinical trial.
    Do you have the capabilities to archive your documentation for the prolonged period, which requires more space, more manpower and little staff turnover?

After many years of experience in conducting and auditing multinational studies including TMF auditing, we have seen a large number of paper-based TMFs, stored at different locations and facilities, maintained by a large variety of people according to different cultures, rules and timelines. At least 90% of those paper TMFs did not match with the new EMA guideline on TMF management.

Most likely, if a TMF of a multination trial is to be established and managed on paper, the required resources for the TMF will let the study costs explode. Comparing costs for storage, control and manpower of an electronic TMF with a paper TMF, is similar to comparing the costs for doing a job with a computer versus using a typewriter.

The main difference is that the typewriter has been removed from most offices 30-40 years ago. It seems that the only reason for using a paper-based TMF is a nostalgic one. Without any doubt, the transition from paper to digital systems requires resources. Nevertheless, postponing this transition will cause even greater economical disadvantages for sponsors and may significantly risk the success of clinical trials and organizations.

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The bad news is “time flies”, the good news is “you are the pilot”. Regulation (EU) 2017/745 (MDR) will apply after a transitional period. Namely, 3 years after entry into force for the Regulation on medical devices, which means spring 2020. The last year to fly into the right direction started!

For the future development of medical devices, the new MDR requires:

– more clinical data;

– more robust data;

– more transparency;

– minimization of patient risks;

– better control of entire life-cycle of the medical devices.

Even though the MDR will not make the medical device world in Europe perfect, it is useless to complain. The system will be changed, and it will become more like the US system, where medical devices fall under the US drug law (CFR). Consequently, some medical devices will be removed from the market, while others will move into another risk-class. Manufacturers will need to conduct 10 times more clinical trials with their new products to receive a CE mark, which will make the medical device development more expensive. In the past many manufacturers made rough estimations on sample sizes for their trials based on the nonvalid statements of notified bodies. In future a powered sample size calculation will be required. Nevertheless, if biostatisticians qualified in  medical devices trials will be involved, we do not expect dramatic  increase in the size of the medical device trials. However, the results of these future trials should be much more powerful compared to the past.

We can see also a lot of cost saving potential for the medical device companies such as:

– moving their trials from the high cost regions to central and eastern Europe, a region that is which more cost-effective for clinical trials;

– involvement of new, highly motivated clinical sites which are much more effective compared to “old professors” (key opinion leaders serving as key opinion leaders for all, even competing companies anyway);

– changing from paper to electronic documentation as nowadays eCRFs are less expensive compared to paper CRFs;

– change from onsite monitoring to remote monitoring, especially for low or medium risk devices;

– change from manual monitoring to statistical monitoring as software can check data better than people;

– planning and designing trials more professionally, having in mind that clinical product development is no academic research.

Yes, the costs of clinical development of medical devices will increase, but as pilots should not choose the way through the thunder storm, you should not choose the expensive way into the unknown. Clinical development of medical devices might be new for many medical device companies however thousands of clinical device trials have been already performed and experienced people and companies exist. Hence do not think you need to reinvent the wheel.

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Why do so many companies run their clinical studies like driving with the car through the fog?

In no other industry can you find so many extremely smart people with excellent ideas to help patients, but when the clinical trial phase starts, many of those intelligent people start playing roulette. Millions of Dollars are spent to see at the end of the trial, if the results are positive in terms of efficacy and safety. If not, all money is gone. And errors during measuring or recording efficacy or safety can quickly turn a study heading the right way into one unable to show the desired outcome.




In most studies it is quite simple to get a better view into the data fog. Nowadays, statistical monitoring can show how our data look like during the whole course of the study and quickly identify spurious data or systematic errors before it is too late. Sponsor who use the foggy way of driving a clinical trial should not complain about the high risk of clinical research but think about more intelligent ways of conducting it. It is not enough to have smart people, people need to do smart things.

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