In Europe, a clinical evaluation report (CER) is now a key element in assessing the fitness of a medical device for clinical use. It documents the clinical evidence that supports a medical device licensing application. After a successful application, it is regularly updated to enable the medical device to remain on the market. The updated CER contains a reassessment of the device's safety and clinical performance, using evidence actively acquired by the manufacturer during the postmarketing clinical follow-up (PMCF).
For device manufacturers, and indeed for the regulatory assessors (notified bodies), the CER has always been a particular challenge. Prior to 1993, documentation of a medical device's clinical efficacy and safety was given much less attention than the documentation of its manufacture and quality. Since the release, in 1993, of the EU Directive 93/42/EEC, the importance of clinical evidence in the licensing of medical devices has increased as the directive went through subsequent amendments and the MEDDEV series of EU guidelines were released.
Now, there is the EU Medical Device Regulations (MDR), released last year, with its increased requirements on clinical evidence acquisition and documentation. The challenge for manufacturers and assessors is now greater than before.
The clinical evidence acquisition and documentation requirements of the EU MDR are essentially derived from the EU guideline, MedDev 2.7/1 revision 4 (EU-2016), released in 2016, which provided much needed guidance on the process of clinical evaluation and on the content of the CER. Appendix A9 of the guideline provides details on the content and format of the CER, which had been missing in previous versions.
However, much of what is prescribed concerning CER content is very familiar to medical writers experienced in writing submission documents for medicinal drugs. The processes described in the 2016 guideline are rooted in the principles of evidence-based medicine, which are being applied on a daily basis by medical writers who create regulatory submission documents for medicinal drugs, such as the clinical overview of the ICH-CTD.
Similar to the clinical overview, the CER contains an evidence-based assessment of efficacy and safety, and a benefit-risk analysis. It also contains a state-of-the-art review of the clinical setting in which the device is to be used. It succinctly reviews current knowledge of the targeted medical condition, with reference to relevant guidelines or international standards, current treatments and precisely what existing clinical needs would be met - or, in the case of a licence renewal, are being met - by the medical device under review.
Source documents include the most recent systematic reviews, current clinical guidelines and relevant international standards, and, possibly, solicited clinical expert statements.
For licensing, the safety and clinical performance of a medical device must conform to specific 'Essential Requirements', as discussed in Appendix A7 of the 2016 EU guideline. It identifies four aspects of a medical device's safety and clinical performance that are to be evaluated and then reported in the CER:
Other factors are also relevant, such as whether another identical or similar device is already on the market and in clinical use, which reduces the level of risk of introducing the new device and, consequently, reduces the required degree of clinical evaluation.
During the PMCF, all four aspects of the medical device's safety and clinical performance are reassessed and the results are incorporated into the CER. This includes an updated systematic review of the published literature, including any new clinical guidelines and standards. For some devices, the manufacturers must also initiate clinical investigations.
In the CER, the new data is assessed in regard to whether it affects the IFU or impacts on how well the device meets the relevant requirements. Submission of an updated CER is required annually for high-risk or relatively new devices and less frequently for others, with the frequency of updating decided in discussions with the notified body.
The CER is a major part of the clinical evaluation and, in many cases, the sole component. Here are three different possible scenarios that would determine the CER content:
The CER author needs to be aware of the assessors' expectations when deciding the scope of the CER. Ideally, the CER author should have direct contact with the notified body but, if not, will need information from the manufacturer on any prior discussions with the designated CER reviewer.
It is particularly important to clarify the extent of the systematic literature review. The guideline refers in detail to the procedures and guidelines for conducting a 'thorough' systematic literature search. But it is crucial to define what constitutes 'all relevant data', as this determines the focus and extent of the literature search. A thorough literature search is often not warranted and an abbreviated search - for example, using PubMed and Google scholar - may be sufficient, but a justification must be given in the CER.
Preparing a CER that meets the current regulations may appear daunting to medical device manufacturers, but help is available from experienced medical regulatory writers that have the skills to get it right.