The Council of the EU’s agreed amendments to the requirements for clinical evaluation reports under the new Medical Device Regulation are substantial. And so are its proposed amendments to clinical investigations and post-market clinical follow up. Sarah Sorrel explains why these amendments are likely to become reality, how companies may be required to adjust and what demands they will have to meet
The proposed changes made by the Council of the European Union’s Employment, Social Policy, Health and Consumer Affairs Council (EPSCO) last month to the European Commission’s texts for a Medical Device Regulation are intended to raise the bar for obtaining the CE marking, both in terms of quality and quantity of clinical data for all devices.
If adopted, they will create potentially complex and costly new measures for all parties concerned – manufacturers, notified bodies and competent authorities (CAs).
The most burdensome proposed changes are for manufacturers of high risk devices (implantable and Class III) with the need for more clinical investigations and the introduction of an additional so-called scrutiny procedure by an “expert panel” independent of the notified body.
For all classes of device, clinical indications must be precisely specified and backed by clinical evidence. Labelling with broad indications that is unsubstantiated will no longer be possible.
There are also significant changes to the CA approval process for pre-market studies and supplemental requirements for the conduct and reporting of clinical investigations. Under the Council proposal, manufacturers would have to make public their clinical data prior to CE marking.
In view of the lack of opposition to the measures– except by industry – and Germany to some extent for the “expert panel” – there is a high likelihood that these changes will become reality in the not so distant future.
Following are some of the key changes that would have an impact for manufacturers on cost and timing of CE marking introduced by the Council amendments should they make it through the regulatory adoption process – a process which EU experts predict will be completed by the first half of 2016.
1. An “Expert Panel” To Scrutinize and Advise On CE Marking
By far the most significant and burdensome change in the proposed regulation for implantable and high risk devices is the introduction of an additional Scrutiny Procedure by an “Expert Panel” prior to CE marking. The Panel may also be consulted in advance of CE marking for advice on the clinical development plan. This would institute a mechanism for manufacturers to seek scientific advice at the European level prior to conducting clinical investigations to ensure that the clinical data will meet the requirements of the Regulation. This could be very useful in the case of disruptive technologies. The German opposition to this amendment relates to the cost and practicality of setting up and managing this aspect.
2. CERs: No Equivalence If Not Strict Equivalence For High Risk Devices
Under the current regulations, manufacturers of implantable and Class III devices can invoke clinical, technical and biological equivalence with other manufacturers’ devices from published data. This is commonly termed the literature route and has allowed countless products to be granted CE marking without clinical investigations.
This was somewhat tightened for Class III products following the 2007 amendment to the MDD. Recent experience with several large Notified Bodies shows that the equivalence possibilities are narrowing somewhat.
However, under the proposed regulations, equivalence is no longer an option except in the case of strict equivalence. In future, the equivalence argument will only be acceptable if the device is an iteration of a previous device by the same manufacturer. Otherwise, the manufacturer will have to show proof of a contractual agreement allowing it to use another manufacturer’s clinical data which will be the exception rather than the rule.
3. Modified CA Approval Procedure And Timelines
One of the most extensive changes proposed by the Council concerns the Notification procedure for clinical investigations of non CE-marked devices.
At present, this notification procedure is different in each EU member state without exception, making the process very complicated, especially for multi-centre trials involving several member states. Many countries have a specific application form that is different from one country to the next, and that needs to be filled out in the local language. Germany, for example, requires a full copy of all pre-clinical reports whereas summary reports are acceptable by others.
Timelines also differ. In some countries, the process can be carried out in parallel with the Ethics Committee procedure. The shortest timeline is in France where approval is possible in 60 days if there are no questions. In other countries such as Poland, the two procedures are sequential. Furthermore, as Poland requires a signed contract before EC submission, timelines can easily extend to six months. Needless to say, the current situation is very complex and labour intensive for manufacturers.
Under the Council amendments, measures would be taken not only to standardize the notification procedure, but to allow a single member state competent authority (“coordinating member state”) to be notified in the case of multi-centre trials involving several member states. This would greatly simplify and streamline the process. On the other hand, the proposal enables an extension of the 60- day waiting period in the current Directive by an additional 20 days in order to consult “experts” if required. A major advantage would be the elimination of the multiple sets of questions by CAs that is presently occurring with the existing legislation.
4. Clinical Study Reports To Be Publicly Available Before CE marking
This is a significant change compared to the current EU regulatory system which is totally opaque with regard to the clinical data that is used for CE marking. Presently, competent authorities may request a copy of the final report individually, but there is no mechanism for sharing the information amongst CAs, and the information is not public unless it results in a scientific publication. Under the proposed regulation, the clinical study report and its summary would have to be uploaded in the European electronic database to be viewed by all, including the public – and this prior to CE marking. This is akin to a system currently in force in France where clinical evaluations for reimbursement approval of medical devices are posted on the website of the Haute Autorité de Santé ( www.has-sante.fr).
5. Legal Representation For Clinical Investigations
Currently, only some of the member states require a Legal Representative for clinical investigations of non CE marked devices. The Council proposal suggests that Legal Representation should be mandatory for all multi-country trials.
6. Damage Compensation For Patients
Many but not all member states currently have statutory insurance requirements for pre-market clinical investigations. The Council proposes that all member states put into place some form of requirement for compensation to patients suffering damage due to participation in a clinical investigation of a non CE marked device.
7. Strengthening Of Patient Rights
The proposal would introduce certain fundamental aspects of patient protection into the law such as personal data protection, as well as provisions from the Declaration of Helsinki as amended with regard to patient withdrawal and trials involving vulnerable populations or emergency treatment.
8. Serious Adverse Event Reporting
Under the proposal, reporting of SAEs to competent authorities would go back to those suspected or confirmed as device or procedure related, rather than all SAEs as is currently the case.
9. Competent Authority Audits of Clinical Investigational Sites
Although some CA audits of trial sites are starting to occur in some member states (for example, Germany, Switzerland, Austria and France) the practice is not widespread. The proposed changes to the Regulation would require all member states to inspect investigation sites to ensure trials are being conducted according to the Regulations and to the Clinical Investigation Plan.
Although there are a lot of changes to the clinical aspects of the CE marking process, especially for implantable and Class III devices, most are needed and reasonable if the system is to be maintained. Some changes will actually streamline the process such as the proposed CA notification process for clinical investigations. The details concerning the Expert Panel are still an important unknown. However, on balance, Europe will remain an attractive location for development, CE marking and initial launch of new medical technology.
Sarah Sorrel is Founder and President of MedPass International, a medical device clinical research organization based in France. She can be contacted at firstname.lastname@example.org