Revised Guidance for Clinical Evaluation in the EU
A new revision of MEDDEV 2.7.1 is now available. This revised guidance is consistent with the increased scrutiny of medical devices and the Notified Bodies (NB) by the Joint Assessments from the Competent Authorities. This has led to a review the Notified Body requirements over clinical evaluation. This revision clarifies these requirements, so that there is greater transparency and fewer 'invisible requirements'.
Effectively, this revision of the guidance represents a complete re-write. The new document can be considered more instructive, but also more prescriptive in particular regarding the use of evidence from equivalent devices. However, this version does not yet address the changed requirements that will soon be published following the new Medical Device Regulations (MDR).
Clinical Evaluation throughout device lifecycle is a key theme running throughout this revision. For initial CE Marking (and other Regulatory approvals - TGA, HSA, CFDA ...), a Clinical Evaluation Report (CER) is required to demonstrate that there is 'sufficient clinical evidence' to demonstrate conformity with the essential requirements covering clinical performance and clinical safety. Importantly, 'sufficient clinical evidence' is newly defined in the latest revision of this Guidance. In the post-market phase, the PMS data (thought complaints, adverse events, post-market clinical follow-u studies, etc.) should be reviewed in a timely manner confirm the risk/benefit profile, and the clinical safety & performance of the device. These data are required to be fed into the clinical evaluation process.
Whilst the document is a complete re-write with significant changes, some are deemed to have most impact on manufacturers.
Demonstration of equivalence is one of the largest changes in this revision, and is now significantly more challanging. Most critical is the requirement that all of the three general criteria (Clinical, Technical, Biological) must be fulfilled by a single device for an equivalence argument to be allowed. In addition, the manufacturer is expected to include the supporting non-clinical information (e.g. pre-clinical reports) in the technical documentation of the device. In order to be able to do this, the manufacturer must have complete access to (own) the equivalence device Technical File/Design Dossier. Additionally, it is important to realise that only clinical data that conforms to the requirements of MDD/AIMD are considered as relevant. Therefore, if non-CE Marked devices are to be claimed as equivalent, the manufacturer must justify any issues concerning differences in patient population or clinical practise between the jurisdictions where the product is approved and the EU. Obviously, this may lead fewer manufacturers being able to justify that the Essential Requirements are met by clinical literature and clinical experience data alone.
'Usability for the intended users' is now specifically called-out to be considered by evaluators in the clinical evaluation. More critical evaluation of the performance testing and data to support usability will likely be the result of this shift in focus.
The frequency for updating the CER is also much more prescriptive in this latest revision. The manufacturer must define and justify the frequency, based on “significant risk” of the device, as well as how “well established” it is (both new concepts described in this revision). This revision now states that the CER must be updated at least annually if the device includes “significant risk” or is not “well established”, and every 2-5 years if device has no “significant risk” and is well established; this frequency must be justified by the manufacturer and should be coordinated with their Notified Body with regard to their expectations for renewal of certificates.
The qualification of the evaluators of clinical data have also increased in this revision of the guidance. In addition to the existing requirements in Rev. 3, it is also specified they should have knowledge of:
Clinical study design
Biostatistics
Regulatory requirements
Experience in medical writing
Furthermore, they must have a higher degree and 5 years of documented professional experience or 10 years of documented professional experience if a higher degree is not a prerequisite for a given task.
However, there is an escape clause for cases where the manufacturer can document and justify deviations from the above.
Sample size and additional guidance on how to analyse the clinical data to show that it meets the Essential Requirements are also changed in this latest revision. For example, it now makes the point that to demonstrate that there are no unacceptable undesirable side effects, studies must be sufficiently large to have a reasonable probability of seeing such side-effects. As the frequency of the side effect in the population decreases, this leads to dramatic increases in the number of subjects required. Thus larger pre-market pivotal studies for medical devices are expected than typically seen in the past, as notified bodies already start to exercise this requirement.
The role and actions required by the notified bodies are also specified in this revision. Some of the main changes are with regard to the required QMS processes the notified body must have for the assessment of CERs, as well as the internal expertise they must have available. In addition, they are now required to write a Clinical Evaluation Assessment Report (CEAR) in all cases (this can be part of the design dossier or technical file report, if one is created).
In summary, this revision is expected lead to more clinical studies, probably of larger size, and notified bodies will be looking more closely at how all the Essential Requirements are met, including those with regard to usability. The Clinical Evaluation Reports themselves will need to be updated more frequently, written and reviewed by more highly qualified evaluators, and more closely integrated with the various stages of the product lifecycle.
As no transition period typically being provided for revisions to MEDDEVs, it would be in the manufacturers' best interests to start discussing with their Notified Bodies how they will start implementing these new requirements. Additionally, gap assessments are warranted, to assess the current standard of recently approved devices as additional data or processes may now be required for annual updates of the CERs. Furthermore, manufacturers should consider budget for additional clinical data due to these new requirements.
If you would like to discuss your clinical evidence plans, or your Clinical Evaluation Reports, please contact us to arrange an assessment.
Mark Phillips.