Revised Guidance Document for Clinical Evaluation in the EU [MEDDEV 2.7.1 (rev 4)]

A new revision of MEDDEV 2.7.1 is now available. (EC Guidance).

This revised MEDDEV is generated within a context of increased scrutiny on the Notified Bodies (NB) by the Joint Assessments from the Competent Authorities, which has led to an increase in the level of review the NB exercise over clinical evaluation. It was felt that there was a need to “codify” these requirements, so that the NB are not reviewing/auditing against “invisible” requirements. Hence, the impetus for this new revision.

In essence, the revision of this document represents a complete re-write, with many new appendices and much new guidance.  The new MEDDEV can be considered more instructive, but also more prescriptive in particular regarding the use of evidence from equivalent devices. It is not yet addressing the changed requirements that will soon see the light in the new MDR where earlier this week consensus was reached in the trilogue debates. Once the new wording of the MDR will become available, the clinical workgroup from the MDEG is considering to initiate a further revision to align to the upcoming legal requirements.

Whilst the document is a complete re-write with massive changes, some are deemed to have most impact on manufacturers.

In an enhanced view on the review of clinical claims, “Usability for the intended users” is now specifically included in the list of things 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.

Next, “Clinical Evaluation throughout device lifecycle” is a key theme running throughout this revision. During the development phase, R&D are guided by clinical evaluation and risk management. Clinical evaluations might be carried out to define the needs regarding clinical safety and performance of the device, as well as to assess the data which exists and any gaps in those data (which may need to be filled by a clinical investigation). For initial CE Marking, a clinical evaluation report (CER) is required to demonstrate that there is “sufficient clinical evidence” (a new definition in this MEDDEV) to demonstrate conformity with the essential requirements covering clinical performance and clinical safety, as well as to identify any aspects which need to be addressed through post-market surveillance (PMS). In the post-market phase, these PMS data should be reviewed to continuously 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 in a timely manner.

The frequency for updating the CER is also much more prescriptive now. 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 to 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 NB with regard to their expectations for renewal of certificates.

This is an important change that in most companies will lead to a revision of their approach for continuous assessment of PMS and clinical data; with the integration of the continuous improvement elements into the regulatory science, a huge increase in resourcing is expected to be needed.

The requirements for the qualification of the evaluators of clinical data have also increased. As well as those from rev 3, it is also specified they should have knowledge of clinical investigation design and biostatistics, regulatory requirements and 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. There is an escape clause for cases where the manufacturer can document and justify deviations from the above.

With regard to the scoping of CERs, as in rev 3, the scope for the clinical evaluation should be based on the essential requirements (ER) that need to be addressed. Annex 7 now gives lots of additional guidance on how to analyse the clinical data to show that it meets the ERs. For example, it now makes the point that to meet ER6 of the MDD (ER 5 AIMD) – undesirable side effects -  studies must be sufficiently large to have a reasonable probability of seeing such side-effects in the sample. As the frequency of the side effect in the population decreases, this leads to dramatic increases in the number of subjects required. Thus larger first in men and pivotal studies for medical devices are expected than typically seen in the past, as notified bodies already start to exercise this requirement.

One of the largest changes in this revision, the demonstration of “equivalence” is much harder now. Most critical is the requirement that all of the three general criteria (Clinical, Technical, Biological) must be fulfilled by a single device now for “equivalence” 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 i.e. the manufacturer must have complete access to (i.e. “own”) the “equivalence” device Technical File/Design Dossier. Important to realise that in moving forward, the only clinical data that are considered as relevant are those obtained from a medical device that conforms to the requirements of the MDD/AIMD. Thus,  if non-CE Marked devices (e.g. those with US 510k or PMA clearance) are to be claimed as “equivalent”, the manufacturer must justify any issues concerning differences in patient population or clinical practice between the jurisdictions where the product is approved and the EU.

Appendix 2 gives guidance on when clinical investigations are needed. Of course, these are needed for implantables and class III devices (unless otherwise justified) per section 1.1a of Annex X. In addition, however, if the device includes novel technology, a new clinical use for an existing technology, or in case there are any gaps in the clinical data with regard to the identification of the benefits, risks, claims or side effects of the use of the device (including for class I, IIa, IIb devices), the need for a clinical investigation is indicated in rev 4. Obviously, this may lead fewer manufacturers being able to justify that the essential requirements are met by clinical literature and clinical experience data alone.

Finally, the role and actions required by the notified bodies are also specified in this document. 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 then, this revision will lead to more clinical investigations, 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 CER 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. With the publication of this document due imminently, and no transition period typically being provided for the MEDDEVs, it would be in the manufacturers best interests to start discussing with their notified bodies how they will start implementing these new requirements and to start performing their gap assessments and resource needs-assessments now. Urgency on gap assessments is warranted, as manufacturers will be expected to budget for additional clinical data asap; hence the assessment will need to feed into the budget plans for next year if clinical studies might need to be initiated in 2017.

Check also our whitepaper about this subject: MEDDEV 2.7.1 Rev4 Will your CER meet new requirements?

 

 

 

Written by: Anna Pietersma, Principal Consultant Clinical Evaluation at Qserve Consultancy BV and Keith Morel, VP Regulatory Compliance at Qserve Group US.

 


 
Keith Morel
Anna Pietersma
Post date: May 27, 2016
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